{"gene":"PELP1","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2001,"finding":"PELP1 was identified as a coactivator of estrogen receptor alpha (ERα). It physically interacts with ERα and with general transcriptional coactivators p300 and CBP, and enhances 17β-estradiol-dependent transcriptional activation from estrogen response elements in a dose-dependent manner. PELP1 contains nine NR-interacting LXXLL motifs, a zinc finger, and glutamic acid- and proline-rich regions.","method":"Co-immunoprecipitation, reporter gene assays (ERE-luciferase), Western blotting, tissue expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, reporter assays, and domain characterization; foundational cloning paper independently replicated across many subsequent studies","pmids":["11481323"],"is_preprint":false},{"year":2003,"finding":"MNAR/PELP1 acts as a scaffold protein mediating ERα-Src interaction: MNAR interacts with the SH3 domain of cSrc via its N-terminal PXXP motif, and with ERα via two N-terminal LXXLL motifs. Mutation of the PXXP motif abolished MNAR-induced Src activation and ER transcriptional stimulation. ERα interacts with Src's SH2 domain via phosphotyrosine 537, and this complex is further stabilized by MNAR-ER interaction. Mutation of LXXLL motifs prevented ER-MNAR complex formation and eliminated Src/MAPK pathway activation.","method":"Mutational analysis of MNAR and ERα, co-immunoprecipitation, functional kinase activation assays, reporter gene assays","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — structure-function mutagenesis of key motifs combined with functional readouts, independently replicated in subsequent studies","pmids":["14963108"],"is_preprint":false},{"year":2003,"finding":"PELP1 physically associates with retinoblastoma protein (pRb) via pRb's C-terminal pocket domain. PELP1 overexpression leads to persistent hyperphosphorylation of pRb at Ser-807/Ser-811 in an E2-dependent manner, enhances progression to S phase, and potentiates cyclin D1 expression. PELP1/pRb interaction is required for maximal PELP1 coactivation function and is modulated by antiestrogen agents.","method":"Co-immunoprecipitation, stable overexpression in MCF-7 cells, phospho-specific pRb antibodies, flow cytometry, reporter gene assays with mutant pRb cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, domain mapping, mutant cell lines, multiple orthogonal methods in one study","pmids":["12682072"],"is_preprint":false},{"year":2004,"finding":"PELP1 localizes to the nucleus, associates with chromatin and nuclear matrix fractions, and is recruited to 17β-estradiol-responsive promoters upon ligand stimulation. PELP1 interacts with histones H1 and H3 (with preference for H1) via its C-terminal region. PELP1 overexpression increases histone acetyltransferase activity and micrococcal nuclease sensitivity of ERE-containing nucleosomes. A PELP1 mutant lacking the H1-binding domain acts as a dominant negative, blocking ERα-mediated transcription. PELP1 displays cyclic association and dissociation from promoters in opposite phase to histone H1, suggesting a role in chromatin remodeling via H1 displacement.","method":"Subnuclear fractionation, confocal microscopy, ChIP, far Western analysis, deletion analysis, histone acetyltransferase enzymatic assay, micrococcal nuclease sensitivity assay, dominant-negative mutant studies","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including enzymatic assays, far Western, ChIP, and functional dominant-negative validation in one study","pmids":["15374949"],"is_preprint":false},{"year":2004,"finding":"PELP1 functions as a corepressor of multiple nuclear receptors and non-NR transcription factors (GR, Nur77, AP1, NF-κB, TCF/SRF) in the absence of ER. The N-terminal leucine-abundant region of PELP1 interacts with HDAC2 and exhibits repressive activity when tethered to chromatin. The C-terminal glutamic acid-abundant region binds hypoacetylated histones H3 and H4, preventing their acetylation. ER binding reverses PELP1's role to promote histone hyperacetylation.","method":"Reporter gene assays, co-immunoprecipitation, domain mapping, chromatin tethering assays, cell proliferation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain mapping with co-IP and functional reporter assays using multiple NR/transcription factor contexts","pmids":["15456770"],"is_preprint":false},{"year":2005,"finding":"Cytoplasmic localization of PELP1 (PELP1-cyto mutant) confers hypersensitivity to estrogen, resistance to tamoxifen, and tumorigenicity in nude mice. Cytoplasmic PELP1 shows increased association with Src, enhanced MAPK activation, constitutive AKT activation, and interaction with the p85 subunit of PI3K leading to PI3K activation. Cytoplasmic PELP1 also interacts with EGFR and participates in growth factor-mediated ER transactivation.","method":"Engineered cytoplasm-restricted PELP1 mutant, stable MCF-7 cell lines, xenograft tumor assays, co-immunoprecipitation, kinase activation assays, Western blotting","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — engineered localization mutant with multiple functional and biochemical readouts, in vivo xenograft validation","pmids":["16140940"],"is_preprint":false},{"year":2005,"finding":"HRS (hepatocyte growth factor-regulated tyrosine kinase substrate) is a novel PELP1-binding protein identified by yeast two-hybrid screen. HRS sequesters PELP1 in the cytoplasm and inhibits PELP1 coactivation of ER transcription. HRS-PELP1 interaction activates MAPK in an EGFR-dependent but ER/Src/Shc-independent manner.","method":"Yeast two-hybrid screen, co-immunoprecipitation, subcellular fractionation, reporter gene assays, MAPK activation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus functional assays, single lab","pmids":["16352611"],"is_preprint":false},{"year":2005,"finding":"MNAR/PELP1 regulates androgen receptor (AR)-mediated nongenomic signaling. MNAR and AR co-immunoprecipitate via the LXXLL-rich segment of MNAR and the ligand binding domain of AR. MNAR also interacts with Gβ via the same region. Reduction of MNAR expression by RNAi in Xenopus oocytes enhances testosterone-triggered meiosis and MAPK activation, and decreases Gβγ-mediated signaling, implicating MNAR in maintaining meiotic arrest.","method":"RNA interference in Xenopus oocytes, co-immunoprecipitation, transient transfection reporter assays","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus RNAi functional readout in Xenopus physiological model, single lab","pmids":["15831520"],"is_preprint":false},{"year":2006,"finding":"MNAR/PELP1 phosphorylation at Tyr-920 by cSrc is required for interaction with p85 (PI3K regulatory subunit) and E2-induced activation of the PI3K/Akt pathway. Mutation Y920A abolishes MNAR-p85 interaction and PI3K/Akt activation (abrogating E2-induced protection from apoptosis) but does not impair Src/MAPK pathway activation or cell proliferation. Endogenous MNAR, ERα, cSrc, and p85 form a complex in E2-treated MCF-7 cells.","method":"Site-directed mutagenesis, co-immunoprecipitation, in vitro kinase assays, reporter gene assays, cell viability/apoptosis assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis with multiple functional readouts, biochemical reconstitution of the pathway, single lab","pmids":["17194752"],"is_preprint":false},{"year":2006,"finding":"PELP1 functions as a coactivator of RXRα, physically interacting with RXRα both in vitro and in vivo. PELP1 promotes formation and stability of RXRα homodimers on consensus oligonucleotides and enhances RXRα-mediated transcription and apoptosis in response to 9-cis-retinoic acid. PELP1 also coactivates RXRα-PPARγ heterodimers.","method":"Co-immunoprecipitation, EMSA supershift assays, reporter gene assays, stable MCF-7 overexpression, siRNA knockdown, differentiation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo binding plus functional assays, single lab","pmids":["16574651"],"is_preprint":false},{"year":2007,"finding":"PELP1 localizes to autophagosomes in cancer cells treated with resveratrol. The intermediary molecule for PELP1 accumulation in autophagosomes is HRS. Both PELP1 and HRS relocalize to autophagosomes (marked by GFP-LC3) upon resveratrol treatment.","method":"Confocal microscopy, GFP-LC3 autophagic marker, pharmacological autophagy inhibitors (3-methyladenine)","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — live imaging co-localization with autophagic marker plus pharmacological controls, single lab","pmids":["17804729"],"is_preprint":false},{"year":2007,"finding":"PELP1 is recruited to the BCAS3 chromatin locus and activates BCAS3 expression; BCAS3 in turn functions as an ERα coactivator that requires PELP1 to enhance ER transactivation activity. BCAS3 physically associates with histone H3 and P/CAF and possesses histone acetyltransferase activity.","method":"ChIP assays, reporter gene assays, co-immunoprecipitation, siRNA knockdown, stable overexpression","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, co-IP, and functional reporter assays with multiple lines of evidence, single lab","pmids":["17505058"],"is_preprint":false},{"year":2008,"finding":"MNAR/PELP1 interacts with GR in the nucleus (but not cytoplasm) and modulates GR transactivation in a cell-type and concentration-dependent manner: MNAR inhibits GR AF1 (ligand-independent) but potentiates AF2 (ligand-dependent). The region MNAR 884-1130 and the N-terminal 1-400 domain (containing LXXLL motifs) both independently inhibit GR transactivation. This GR regulatory function is independent of c-Src activity.","method":"Co-immunoprecipitation, reporter gene assays, deletion analysis, c-Src inhibitors and knockdown, immunofluorescence","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain deletion mapping with co-IP and reporter assays in multiple cell lines, c-Src independence demonstrated, single lab","pmids":["18682536"],"is_preprint":false},{"year":2008,"finding":"Growth factor signaling promotes phosphorylation of PELP1 via protein kinase A (PKA). PKA directly phosphorylates PELP1 in vitro; mutation of the putative PKA site in PELP1 compromises growth factor-induced ER transactivation, subnuclear localization of PELP1, and PELP1-mediated coactivation function.","method":"In vivo phosphorylation labeling, phospho-substrate specific antibodies, PKA inhibitor (H89), in vitro kinase assays with purified PKA, deletion and site-directed mutagenesis, reporter gene assays","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus mutagenesis plus functional validation, multiple orthogonal methods, single lab","pmids":["18505929"],"is_preprint":false},{"year":2009,"finding":"PELP1 deregulation contributes to increased aromatase expression via activation of aromatase promoter I.3/II. PELP1 is recruited to the aromatase I.3/II promoter as shown by ChIP. PELP1-mediated aromatase induction requires functional Src and PI3K pathways and involves interaction with orphan receptor ERRα and histone demethylases. HER2 signaling enhances PELP1 recruitment to the aromatase promoter.","method":"ChIP assays, reporter gene assays, aromatase activity assays, Western blotting, xenograft and transgenic mouse models","journal":"The Journal of steroid biochemistry and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-based promoter recruitment plus functional signaling pathway requirements, in vivo confirmation, single lab","pmids":["19800002"],"is_preprint":false},{"year":2010,"finding":"PELP1 is a reader of histone H3 methylation marks. PELP1 interacts with the histone lysine demethylase KDM1 (LSD1). Both are co-recruited to ERα target genes. PELP1 depletion affects dimethyl histone modifications (H3K4me2 and H3K9me2) at ERα target genes. PELP1 alters KDM1 substrate specificity from H3K4 to H3K9 dimethylation. Effective demethylation of H3K9me2 requires a KDM1-ERα-PELP1 functional complex.","method":"Co-immunoprecipitation, ChIP assays, siRNA knockdown, in vitro demethylase activity assays, reporter gene assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — enzymatic substrate specificity demonstrated in vitro plus ChIP in vivo, PELP1 identified as histone mark reader, multiple orthogonal methods","pmids":["20448663"],"is_preprint":false},{"year":2010,"finding":"TTLL4 polyglutamylase modifies PELP1 by adding glutamate side chains (polyglutamylation) to PELP1's glutamate stretch region. PELP1 polyglutamylation influences PELP1 interaction with histone H3 and affects histone H3 acetylation. PELP1 interacts with LAS1L and SENP3, components of the MLL1-WDR5 supercomplex involved in chromatin remodeling.","method":"Knockdown of TTLL4 by shRNA, immunoprecipitation, co-immunoprecipitation, cell growth assays, correlation of TTLL4 expression with PELP1 polyglutamylation levels","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — identification of novel PTM with biochemical consequences for histone interaction, complex membership identified, single lab","pmids":["20442285"],"is_preprint":false},{"year":2010,"finding":"PELP1 is a novel substrate of cyclin-dependent kinases (CDKs). Ser477 and Ser991 of PELP1 are CDK phosphorylation sites identified by site-directed mutagenesis and in vitro kinase assays. PELP1 is hyperphosphorylated during cell cycle progression. PELP1 CDK-site mutants exhibit defects in E2-mediated cell cycle progression and oncogenic functions in vivo. PELP1 modulates E2F1 transactivation and is recruited to pRb/E2F target gene promoters, facilitating ER-cell cycle machinery crosstalk.","method":"Site-directed mutagenesis, in vitro CDK kinase assays, phospho-specific antibody, ChIP assays, reporter gene assays, stable cell lines, xenograft models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, ChIP, and in vivo functional validation, multiple orthogonal methods, single lab","pmids":["20807815"],"is_preprint":false},{"year":2011,"finding":"PELP1 localizes to the nucleolus and is associated with active ribosomal RNA transcription. PELP1 nucleolar localization is cell-cycle dependent (highest in S and G2 phases) and regulated by CDK activity. PELP1 depletion decreases pre-rRNA expression. PELP1 is recruited to the promoter regions of rDNA (ChIP) and is needed for optimal rDNA transcription. PELP1 domains required for nucleolar localization are essential for rDNA reporter activation.","method":"Pharmacological inhibitors, confocal microscopy, cell synchronization, CDK site mutants, siRNA, reporter gene assays (rDNA-luciferase), ChIP assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization by microscopy linked to functional consequence via ChIP and reporter assays, siRNA knockdown, multiple orthogonal methods","pmids":["21695158"],"is_preprint":false},{"year":2012,"finding":"PELP1 forms a protein complex with AR, ERβ, and PELP1 on AR-responsive DNA elements in prostate cancer cells in response to E2. This complex enables E2-induced transcription of AR-responsive genes and E2-stimulated cell proliferation. Knockdown of PELP1, AR, or ERβ blocks complex assembly, blocks E2-induced AR gene activation, and blocks proliferation.","method":"Co-immunoprecipitation, ChIP assays, siRNA knockdown, reporter gene assays, cell proliferation assays","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and co-IP demonstrate complex on DNA, functional siRNA knockdown, single lab","pmids":["22403175"],"is_preprint":false},{"year":2013,"finding":"PELP1 binds to the promoters of miR-200a and miR-141 and represses their expression by recruiting histone deacetylase 2 (HDAC2). PELP1 knockdown reduced ZEB1 and ZEB2 expression and metastatic potential. Re-introduction of miR-200a and miR-141 mimetics reversed PELP1 target gene expression and reduced PELP1-driven migration/invasion in vitro and in vivo.","method":"ChIP assays, whole genome miR array, siRNA knockdown, HDAC inhibitor assays, Boyden chamber assays, xenograft tumor models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-based promoter recruitment, pharmacological inhibition, genetic rescue with miR mimetics, in vivo validation, multiple orthogonal methods","pmids":["23975430"],"is_preprint":false},{"year":2013,"finding":"PELP1 is a reader of histone arginine methyl modifications. PELP1 functionally interacts with the arginine methyltransferase CARM1; their interaction is enhanced by ERα. PELP1-CARM1 interactions synergistically enhance ERα transactivation. PELP1 alters histone H3 arginine methylation status at ERα target gene promoters as shown by ChIP. PELP1 knockdown decreases CARM1-driven arginine dimethylation in vivo.","method":"Histone peptide array, co-immunoprecipitation, ChIP assays, pharmacological CARM1 inhibition, siRNA knockdown, reporter gene assays, xenograft models","journal":"Carcinogenesis","confidence":"High","confidence_rationale":"Tier 2 / Moderate — histone peptide array binding, co-IP, ChIP, functional reporter assays with pharmacological and genetic inhibition, in vivo confirmation, single lab","pmids":["23486015"],"is_preprint":false},{"year":2013,"finding":"PELP1 interacts with the arginine methyltransferase PRMT6 and modifies PRMT6 functions. PELP1 and PRMT6 are co-recruited to ERα target genes; PELP1 knockdown affects enrichment of histone H3R2 dimethylation. PELP1 co-localizes with splicing factor SC35 at nuclear speckles and participates in alternative splicing, binding RNA with preference for poly-C sequences.","method":"RNA-sequencing, co-immunoprecipitation, ChIP assays, RNA binding assays, immunofluorescence co-localization, siRNA knockdown, reporter gene assays","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, and RNA binding demonstrated, single lab with multiple methods","pmids":["24447537"],"is_preprint":false},{"year":2014,"finding":"PELP1 serves as a scaffold for ER/PR/PELP1/IGF1R-containing transcription complexes in breast cancer cells. Unliganded PR-B enhances estradiol-responsive ER transcription via scaffolding these complexes on ERE-containing promoters. The ER/PR/PELP1 complex was also detected in human breast cancer samples.","method":"ChIP assays, co-immunoprecipitation, stable cell line expression, growth assays, microarray gene expression, immunoprecipitation from patient tumor samples","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus co-IP in cell lines plus patient tumor confirmation, single lab","pmids":["24469035"],"is_preprint":false},{"year":2014,"finding":"PELP1 cross-talks with the mTOR signaling pathway. PELP1 knockdown reduces activation of mTOR downstream signaling components. PELP1 overexpression excessively activates mTOR signaling. mTOR signaling complex proteins are detected in PELP1 immunoprecipitates.","method":"Co-immunoprecipitation, Western blotting (phospho-mTOR pathway markers), siRNA knockdown, xenograft tumor models, mTOR inhibitor treatment","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single co-IP plus functional pharmacological evidence, in vivo validation, single lab","pmids":["24688046"],"is_preprint":false},{"year":2015,"finding":"PELP1 interacts with mutant p53 (MTp53), regulates its recruitment to target gene promoters, and alters epigenetic marks at those promoters. PELP1 knockdown reduces MTp53 target gene expression and increases apoptosis upon genotoxic stress. PELP1 regulates E2F1 stability in a KDM1A-dependent manner. PELP1 phosphorylation at S1033 plays an important role in its oncogenic functions in TNBC cells.","method":"Co-immunoprecipitation, ChIP assays, siRNA knockdown, reporter gene assays, flow cytometry","journal":"Breast cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, and functional readouts with phospho-mutant, single lab","pmids":["25788226"],"is_preprint":false},{"year":2016,"finding":"PELP1 interacts with glucocorticoid receptor (GR) and is induced in a HIF-dependent manner in response to hypoxia or dexamethasone. PELP1 is part of a phospho-GR/HIF/PELP1 complex that assembles on the BRK promoter, promoting Brk expression in triple-negative breast cancer.","method":"ChIP assays, co-immunoprecipitation, Western blotting, GR ligand treatments, hypoxia conditions, siRNA knockdown","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-based promoter occupancy plus co-IP for complex formation, single lab","pmids":["26825173"],"is_preprint":false},{"year":2016,"finding":"Cytoplasmic localization of PELP1 up-regulates IKKε and increases phosphorylation of the NF-κB subunit RelB. PELP1-cyto-expressing mammary epithelial cells secrete factors that activate macrophages in a paracrine manner, and those activated macrophages produce conditioned medium that drives HMEC migration. This migration is reduced by IKKε shRNA knockdown.","method":"Gene expression analysis, Western blotting, conditioned medium experiments, shRNA knockdown, Boyden chamber migration assays, PELP1-cyto mutant cell lines","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — engineered PELP1-cyto mutant, paracrine assay, IKKε genetic knockdown confirms pathway, single lab","pmids":["27881676"],"is_preprint":false},{"year":2018,"finding":"Cytoplasmic PELP1 forms a complex with AIB1/SRC-3, identified as a novel binding partner. Cytoplasmic PELP1 expression elevates basal phosphorylation (Thr24 activation) of AIB1, enhances ALDH+ tumorsphere formation, and upregulates specific target genes independently of hormone stimulation. Direct AIB1 knockdown or pharmacological inhibition (SI-2) abrogates cytoplasmic PELP1-induced tumorsphere formation.","method":"Co-immunoprecipitation, tumorsphere assays (ALDH+ sorting), shRNA knockdown, Western blotting, syngeneic in vivo tumor studies","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional genetic and pharmacological inhibition, in vivo confirmation, single lab","pmids":["29348189"],"is_preprint":false},{"year":2021,"finding":"Cytoplasmic complexes of PELP1 and SRC-3 modulate breast cancer stem cell expansion through upregulation of HIF-activated metabolic target genes PFKFB3 and PFKFB4. PELP1 physically interacts with PFKFB3 and PFKFB4 proteins. Inhibition of PFKFB3/4 kinase activity blocks PELP1-induced tumorsphere formation and PELP1/SRC-3 protein-protein interactions. Cytoplasmic PELP1 increases both glycolysis and mitochondrial respiration as measured by Seahorse metabolic assays.","method":"Co-immunoprecipitation, Seahorse metabolic assays, tumorsphere assays, PFKFB inhibitors, shRNA knockdown, xenograft and patient-derived organoid models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus Seahorse functional metabolic readout plus genetic and pharmacological inhibition, single lab","pmids":["34103681"],"is_preprint":false},{"year":2021,"finding":"PELP1 interacts with TFAP2C (transcription factor AP-2γ). PELP1 functions as a coactivator of TFAP2C and mediates TFAP2C-induced changes in histone methylation at the RET promoter, increasing RET expression and downstream AKT and ERK pathway activation. PELP1 knockdown abrogates TFAP2C-driven breast cancer progression in vivo.","method":"Co-immunoprecipitation, RNA-seq, ChIP assays, reporter gene assays, siRNA knockdown, Western blotting, xenograft models","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, functional reporter assays, and in vivo xenograft validation, single lab","pmids":["33269540"],"is_preprint":false},{"year":2022,"finding":"PELP1 is the central scaffold for the human Rix1 complex, whose members include WDR18, TEX10, and SENP3. The cryo-EM structure of the PELP1 Rix1 domain–WDR18 subcomplex was determined at 2.7 Å, revealing an interconnected tetrameric assembly and the architecture of PELP1's eleven LxxLL motifs, none of which are in a conformation that would support steroid receptor binding within this complex. Association with WDR18 may direct PELP1 activity away from SR coactivation.","method":"Cryo-EM structure determination (2.7 Å), in vitro reconstitution of mammalian Rix1 complex, identification of stable sub-complex","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure with in vitro reconstitution; directly resolves LxxLL motif architecture and demonstrates incompatibility with SR binding in this complex context","pmids":["36351913"],"is_preprint":false},{"year":2022,"finding":"SETDB1 interacts with PELP1, identified initially by yeast two-hybrid screen and confirmed by co-immunoprecipitation and GST pull-down. PELP1 is necessary for SETDB1-mediated Akt methylation and phosphorylation. SETDB1 overexpression promotes tamoxifen resistance in breast cancer cells, and PELP1 knockdown abolishes these effects.","method":"Yeast two-hybrid screen, co-immunoprecipitation, GST pull-down, in vitro methylation assays, Western blotting, xenograft models","journal":"Breast cancer research : BCR","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — yeast two-hybrid plus GST pull-down plus co-IP plus in vitro methylation assay plus in vivo xenograft, multiple orthogonal methods, single lab","pmids":["35395812"],"is_preprint":false},{"year":2022,"finding":"SMIP34, a small-molecule inhibitor of PELP1, directly binds to PELP1 and induces its degradation via the proteasome pathway. SMIP34 inhibits PELP1 oncogenic functions including extranuclear signaling (ERK, mTOR, S6, 4EBP1), ribosomal biogenesis functions (cMyc, LAS1L, TEX10, SENP3/Rix complex), and suppresses ER+ breast cancer progression in cell line-derived and patient-derived xenografts.","method":"Yeast two-hybrid screen for PELP1 peptide inhibitors, biochemical binding assays, computational modeling, RNA-seq, Western blotting, xenograft and PDX models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding assay, mechanism of action (proteasome degradation), RNA-seq pathway analysis, and in vivo xenograft and PDX validation, multiple orthogonal methods","pmids":["35950923"],"is_preprint":false},{"year":2025,"finding":"PELP1 serves as the central scaffold of the rixosome complex upon which enzymatic subunits modularly assemble. The C-terminal proline-rich IDR of PELP1 mediates association with the AAA-ATPase MDN1, histones, and SENP3. The glutamic acid-rich region of the PELP1 IDR can chaperone the histone octamer in vitro. An X-ray crystal structure of a short linear motif (SLiM) from the PELP1 IDR bound to SENP3 reveals how PELP1 allosterically activates SUMO protease activity.","method":"X-ray crystallography (SLiM-SENP3 structure), in vitro histone octamer chaperoning assay, biochemical reconstitution of rixosome subunit assembly, structural and functional domain analysis","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Moderate — X-ray structure plus in vitro reconstitution plus enzymatic (SUMO protease) activation assay, multiple orthogonal methods, single recent paper","pmids":["40712028"],"is_preprint":false},{"year":2019,"finding":"PELP1 promotes glioblastoma progression by interacting with and functioning as a coactivator of β-catenin, activating Wnt/β-catenin target gene expression. PELP1 knockdown significantly reduced expression of Wnt/β-catenin pathway genes and improved survival of orthotopic GBM tumor-bearing mice.","method":"Co-immunoprecipitation, RNA-seq, reporter gene assays, siRNA knockdown, orthotopic mouse models","journal":"Neuro-oncology advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus reporter assays plus in vivo validation, single lab","pmids":["32309805"],"is_preprint":false},{"year":2025,"finding":"PELP1 interacts with FHL2 to potentiate transcriptional activation of downstream target genes including CCND1, CCND2, CDK6, ANG, CCL2, and MMP3 in ectopic endometrial stromal cells. PELP1 knockdown inhibited proliferation, angiogenesis, and inflammation in endometriosis models.","method":"Co-immunoprecipitation, siRNA knockdown, animal models, qRT-PCR, Western blotting","journal":"Cell biology international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP study, limited mechanistic follow-up, single lab","pmids":["41165240"],"is_preprint":false}],"current_model":"PELP1 is a large multidomain scaffold protein and proto-oncogene that functions as a coregulator of estrogen receptor alpha (ERα) and multiple other nuclear receptors by: (1) serving as the central scaffold of the rixosome/Rix1 complex (with WDR18, TEX10, SENP3) for ribosome biogenesis and RNA decay, allosterically activating SENP3 SUMO protease activity; (2) reading histone H3 methylation marks (H3K4me2, H3K9me2, arginine methylation) and altering the substrate specificity of KDM1 (LSD1) from H3K4 to H3K9 while recruiting HDAC2 and CARM1 to modulate epigenetic states at ERα target gene promoters; (3) scaffolding rapid non-genomic ER signaling by bridging ERα (via LXXLL motifs) and cSrc (via PXXP/SH3 domain interaction), with subsequent MNAR phosphorylation at Tyr920 by cSrc enabling p85/PI3K recruitment and Akt activation; (4) interacting with pRb, E2F1, and CDKs (phosphorylated at Ser477/Ser991) to regulate cell cycle progression; and (5) acting in the cytoplasm to activate mTOR, MAPK/Src, and metabolic (PFKFB3/4) pathways that drive therapy resistance and cancer stem cell expansion."},"narrative":{"mechanistic_narrative":"PELP1 is a large multidomain scaffold protein that functions both as a nuclear receptor coregulator and as the structural core of a ribosome biogenesis complex, integrating hormone signaling, chromatin modification, and cell cycle control to drive proliferation [PMID:11481323, PMID:20448663, PMID:36351913]. It was first identified as an estrogen receptor alpha (ERα) coactivator that binds ERα through its nine LXXLL motifs and recruits the general coactivators p300/CBP to enhance estradiol-dependent transcription [PMID:11481323]. PELP1 reads histone methylation marks and remodels chromatin at ERα target promoters: it interacts with histones H1 and H3, displaces H1 in cyclic phase with promoter occupancy, and reprograms the demethylase KDM1/LSD1 to switch its substrate specificity from H3K4 to H3K9 while engaging the arginine methyltransferases CARM1 and PRMT6 [PMID:15374949, PMID:20448663, PMID:23486015, PMID:24447537]. Its transcriptional output is context-dependent — acting as a corepressor in the absence of ER by recruiting HDAC2 to bind hypoacetylated histones, and switching to coactivation upon ER binding [PMID:15456770]. Beyond the nucleus, PELP1 serves as a scaffold for rapid non-genomic signaling, bridging ERα via LXXLL motifs and cSrc via an N-terminal PXXP motif to activate Src/MAPK, and after cSrc phosphorylates it at Tyr920 it recruits the p85 subunit of PI3K to drive Akt activation [PMID:14963108, PMID:17194752]. Cytoplasmic restriction of PELP1 confers estrogen hypersensitivity, tamoxifen resistance, and tumorigenicity through constitutive Src/MAPK, PI3K/Akt, mTOR, and metabolic (PFKFB3/4) signaling and cancer stem cell expansion [PMID:16140940, PMID:24688046, PMID:34103681]. PELP1 is a CDK substrate (Ser477/Ser991) that couples ER signaling to the pRb/E2F cell cycle machinery and to rDNA transcription in the nucleolus [PMID:12682072, PMID:20807815, PMID:21695158]. Structurally, PELP1 is the central scaffold of the human Rix1/rixosome complex with WDR18, TEX10, and SENP3, where its proline- and glutamate-rich intrinsically disordered region chaperones histones and allosterically activates SENP3 SUMO protease activity [PMID:36351913, PMID:40712028]. PELP1's coregulator and scaffolding functions extend to other nuclear receptors (AR, RXRα, GR) and transcription factors (β-catenin, TFAP2C), and it is a validated therapeutic target whose small-molecule inhibitor SMIP34 induces its proteasomal degradation [PMID:15831520, PMID:16574651, PMID:33269540, PMID:35950923, PMID:32309805].","teleology":[{"year":2001,"claim":"Established PELP1's founding identity by showing it physically binds ERα and the p300/CBP coactivators to amplify estrogen-responsive transcription, defining it as a nuclear receptor coregulator.","evidence":"Co-IP, ERE-luciferase reporter assays, and domain mapping identifying nine LXXLL motifs","pmids":["11481323"],"confidence":"High","gaps":["Did not resolve which LXXLL motifs mediate binding","No structural basis for coactivation"]},{"year":2003,"claim":"Resolved how PELP1 scaffolds non-genomic ER signaling, showing it bridges cSrc (via PXXP) and ERα (via LXXLL) to activate Src/MAPK, extending its role beyond transcription into membrane-proximal kinase activation.","evidence":"Motif mutagenesis, co-IP, and kinase/reporter assays in mammalian cells","pmids":["14963108"],"confidence":"High","gaps":["Did not define downstream PI3K branch","Phosphorylation events not yet mapped"]},{"year":2003,"claim":"Connected PELP1 to cell cycle control by showing it binds pRb and promotes its hyperphosphorylation and S-phase entry, linking ER coactivation to proliferative machinery.","evidence":"Co-IP, phospho-pRb antibodies, flow cytometry in MCF-7 cells","pmids":["12682072"],"confidence":"High","gaps":["Kinase responsible for pRb phosphorylation not defined here","Direct vs indirect effect unresolved"]},{"year":2004,"claim":"Defined PELP1's chromatin-remodeling mechanism, showing it binds histones H1/H3, displaces H1 cyclically at promoters, and can act as either coactivator or corepressor via distinct domains binding HDAC2 or hypoacetylated histones.","evidence":"Subnuclear fractionation, ChIP, far Western, HAT assays, MNase sensitivity, dominant-negative and tethering assays","pmids":["15374949","15456770"],"confidence":"High","gaps":["Histone-mark readers not yet identified","Switch mechanism between repression and activation incompletely defined"]},{"year":2005,"claim":"Demonstrated that cytoplasmic PELP1 localization is a driver of therapy resistance and tumorigenicity through constitutive Src, MAPK, AKT, and PI3K activation, mechanistically linking subcellular distribution to oncogenic phenotype.","evidence":"Engineered cytoplasm-restricted mutant, xenografts, co-IP, kinase assays","pmids":["16140940"],"confidence":"High","gaps":["Endogenous determinants of PELP1 localization unknown","Did not define molecular trigger for cytoplasmic accumulation"]},{"year":2005,"claim":"Broadened PELP1's coregulator scope to other steroid receptors and identified cytoplasmic regulators, showing AR/Gβ engagement governs meiotic arrest and HRS sequesters PELP1 in the cytoplasm to restrain ER coactivation.","evidence":"Yeast two-hybrid, RNAi in Xenopus oocytes, co-IP, fractionation, reporter assays","pmids":["15831520","16352611"],"confidence":"Medium","gaps":["Single-lab findings","Physiological relevance of HRS sequestration in human cancer not established"]},{"year":2006,"claim":"Pinpointed the molecular switch for the PI3K/Akt arm, showing cSrc phosphorylation of PELP1 at Tyr920 is required for p85 recruitment and E2-induced Akt-mediated survival, separating this branch from Src/MAPK and proliferation.","evidence":"Site-directed Y920A mutagenesis, co-IP, in vitro kinase, apoptosis assays","pmids":["17194752"],"confidence":"High","gaps":["Other phosphosites not yet characterized","Single-lab reconstitution"]},{"year":2006,"claim":"Extended PELP1 coactivation to RXRα signaling, showing it stabilizes RXRα homodimers and RXRα-PPARγ heterodimers and enhances retinoid-induced transcription and apoptosis.","evidence":"Co-IP, EMSA supershift, reporter and differentiation assays","pmids":["16574651"],"confidence":"Medium","gaps":["Single lab","In vivo retinoid relevance not established"]},{"year":2008,"claim":"Showed PELP1 is integrated into growth factor signaling through PKA phosphorylation that controls its subnuclear localization and coactivation, and clarified that its GR regulation is c-Src-independent and domain-specific.","evidence":"In vitro PKA kinase assays, phospho-mutants, H89 inhibitor, deletion mapping, reporter assays","pmids":["18505929","18682536"],"confidence":"Medium","gaps":["PKA site sequence not fully defined","Cell-type dependence of GR effects unexplained"]},{"year":2009,"claim":"Linked PELP1 to estrogen biosynthesis by showing it is recruited to the aromatase I.3/II promoter via ERRα and histone demethylases to upregulate aromatase, with HER2 enhancing recruitment.","evidence":"ChIP, aromatase activity and reporter assays, xenograft and transgenic models","pmids":["19800002"],"confidence":"Medium","gaps":["Single lab","Direct ERRα-PELP1 contacts not mapped"]},{"year":2010,"claim":"Identified PELP1 as a histone-mark reader that reprograms KDM1/LSD1 substrate specificity from H3K4 to H3K9, providing a mechanistic basis for its bidirectional chromatin effects at ER target genes.","evidence":"Co-IP, ChIP, siRNA, in vitro demethylase assays","pmids":["20448663"],"confidence":"High","gaps":["Structural basis of specificity switch unresolved","Genome-wide scope not mapped"]},{"year":2010,"claim":"Coupled PELP1 to cell cycle and nucleolar function, showing CDKs phosphorylate Ser477/Ser991 to regulate E2-driven proliferation, E2F1 transactivation, and cell-cycle-dependent nucleolar rDNA transcription.","evidence":"In vitro CDK kinase assays, phospho-mutants, ChIP, cell synchronization, rDNA reporter assays, xenografts","pmids":["20807815","21695158"],"confidence":"High","gaps":["How CDK phosphorylation directs nucleolar targeting not fully mechanistic","Link to ribosome biogenesis complex not yet made"]},{"year":2010,"claim":"Revealed a PTM regulating PELP1 chromatin function — TTLL4-mediated polyglutamylation of its glutamate stretch — and first placed PELP1 in chromatin-remodeling complexes with LAS1L and SENP3.","evidence":"shRNA knockdown of TTLL4, immunoprecipitation, co-IP, growth assays","pmids":["20442285"],"confidence":"Medium","gaps":["Functional consequence of complex membership not resolved here","Single lab"]},{"year":2013,"claim":"Expanded PELP1's epigenetic reader/writer activity to arginine methylation (CARM1, PRMT6) and to RNA-level regulation, showing it controls H3 arginine methylation at ER targets, localizes to nuclear speckles with SC35, and participates in alternative splicing.","evidence":"Histone peptide arrays, RNA-seq, co-IP, ChIP, RNA-binding assays, xenografts","pmids":["23486015","24447537"],"confidence":"High","gaps":["RNA-binding specificity beyond poly-C undefined","Splicing program targets incompletely mapped"]},{"year":2013,"claim":"Established PELP1 as a driver of metastasis through epigenetic repression, showing it recruits HDAC2 to silence miR-200a/miR-141, derepressing ZEB1/ZEB2 to promote EMT and invasion.","evidence":"ChIP, miR array, HDAC inhibitors, miR mimetic rescue, Boyden chamber, xenografts","pmids":["23975430"],"confidence":"High","gaps":["Direct PELP1 promoter-binding mode unresolved","Other miRNA targets not surveyed"]},{"year":2014,"claim":"Showed PELP1 scaffolds multi-receptor transcription complexes (ER/PR/IGF1R) and cross-talks with mTOR, integrating hormone and growth-factor pathways to support proliferation.","evidence":"ChIP, co-IP, microarray, patient tumor IP, mTOR inhibitor treatment, xenografts","pmids":["24469035","24688046"],"confidence":"Medium","gaps":["Direct vs scaffolded mTOR contacts unclear","Single-lab co-IP for mTOR association"]},{"year":2015,"claim":"Connected PELP1 to mutant-p53 and TNBC oncogenic programs, showing it regulates MTp53 promoter recruitment and E2F1 stability in a KDM1A-dependent manner, with S1033 phosphorylation important for oncogenic function.","evidence":"Co-IP, ChIP, siRNA, reporter assays, flow cytometry","pmids":["25788226"],"confidence":"Medium","gaps":["S1033 kinase not identified","Single lab"]},{"year":2016,"claim":"Defined hypoxia- and glucocorticoid-responsive and inflammatory roles, showing PELP1 assembles a phospho-GR/HIF complex to induce Brk, and cytoplasmic PELP1 drives IKKε/RelB-mediated paracrine macrophage activation and migration.","evidence":"ChIP, co-IP, hypoxia/dexamethasone treatments, conditioned-medium and migration assays, shRNA","pmids":["26825173","27881676"],"confidence":"Medium","gaps":["Direct PELP1-HIF contacts not mapped","Secreted paracrine factors not identified"]},{"year":2018,"claim":"Identified the cytoplasmic PELP1-AIB1/SRC-3 axis as a driver of cancer stem cell expansion, showing PELP1 elevates AIB1 Thr24 phosphorylation and ALDH+ tumorsphere formation independently of hormone.","evidence":"Co-IP, tumorsphere/ALDH sorting, SI-2 inhibition, shRNA, syngeneic models","pmids":["29348189"],"confidence":"Medium","gaps":["Mechanism of AIB1 activation by PELP1 undefined","Single lab"]},{"year":2021,"claim":"Linked the PELP1/SRC-3 cytoplasmic complex to metabolic reprogramming, showing PELP1 binds PFKFB3/PFKFB4 and increases glycolysis and respiration to sustain stem cell expansion.","evidence":"Co-IP, Seahorse assays, PFKFB inhibitors, tumorspheres, xenograft and organoid models","pmids":["34103681"],"confidence":"Medium","gaps":["Whether PELP1 directly regulates PFKFB kinase activity unclear","Single lab"]},{"year":2021,"claim":"Generalized PELP1 coactivation beyond nuclear receptors to lineage transcription factors, showing it coactivates TFAP2C and β-catenin to drive RET/AKT/ERK signaling and Wnt target gene expression in breast cancer and glioblastoma.","evidence":"Co-IP, RNA-seq, ChIP, reporter assays, orthotopic and xenograft models","pmids":["33269540","32309805"],"confidence":"Medium","gaps":["Direct binding interfaces not mapped","Tissue-specificity of partner selection unexplained"]},{"year":2022,"claim":"Resolved PELP1's structural role as the central scaffold of the human Rix1 complex with WDR18/TEX10/SENP3, with a cryo-EM structure showing its LxxLL motifs are not configured for steroid receptor binding in this context — implying WDR18 association partitions PELP1 away from coactivation.","evidence":"Cryo-EM at 2.7 Å of the PELP1 Rix1 domain–WDR18 subcomplex, in vitro reconstitution","pmids":["36351913"],"confidence":"High","gaps":["How PELP1 partitions between Rix1 and coactivator pools in cells unresolved","Functional output of the rixosome in cancer not directly tested here"]},{"year":2022,"claim":"Identified SETDB1 as a PELP1 partner required for Akt methylation and tamoxifen resistance, and validated PELP1 as a druggable target via SMIP34, which binds PELP1 and triggers its proteasomal degradation, suppressing both extranuclear and ribosome-biogenesis functions.","evidence":"Yeast two-hybrid, GST pull-down, co-IP, in vitro methylation; SMIP34 binding assays, RNA-seq, xenograft/PDX models","pmids":["35395812","35950923"],"confidence":"High","gaps":["SMIP34 binding site on PELP1 not crystallographically defined","Clinical translation not addressed"]},{"year":2025,"claim":"Provided the structural mechanism for PELP1's rixosome scaffolding, showing its C-terminal IDR engages MDN1, histones, and SENP3, that its glutamate-rich region chaperones the histone octamer, and that a SLiM-SENP3 crystal structure explains allosteric activation of SUMO protease activity.","evidence":"X-ray crystallography of SLiM-SENP3, in vitro histone chaperoning, biochemical reconstitution","pmids":["40712028"],"confidence":"High","gaps":["In vivo SUMO substrates of the PELP1-activated rixosome not defined","Integration with PELP1's coactivator functions unresolved"]},{"year":null,"claim":"How PELP1 partitions between its nuclear receptor coactivator, chromatin-remodeling, extranuclear signaling, and rixosome scaffolding roles — and what governs the localization and PTM states that toggle between them — remains the central open question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of how subcellular localization is regulated","Competition between WDR18/Rix1 binding and SR coactivation not quantified in cells","Causative role in any Mendelian disease not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,4,9,30,35]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[15,21]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[3,4,15,21]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,8,31,34]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[34]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[22]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[18]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,27,29]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[22]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,8,5,24]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,4,15,21]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,15,21,20]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[31,34,18]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,17]}],"complexes":["Rix1 complex / rixosome (PELP1-WDR18-TEX10-SENP3)","ERα-cSrc-p85/PI3K non-genomic signaling complex","ER/PR/PELP1/IGF1R transcription complex"],"partners":["ESR1","SRC","KDM1A","CARM1","WDR18","SENP3","RB1","NCOA3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IZL8","full_name":"Proline-, glutamic acid- and leucine-rich protein 1","aliases":["Modulator of non-genomic activity of estrogen receptor","Transcription factor HMX3"],"length_aa":1130,"mass_kda":119.7,"function":"Coactivator of estrogen receptor-mediated transcription and a corepressor of other nuclear hormone receptors and sequence-specific transcription factors (PubMed:14963108). Plays a role in estrogen receptor (ER) genomic activity when present in the nuclear compartment by activating the ER target genes in a hormonal stimulation dependent manner. Can facilitate ER non-genomic signaling via SRC and PI3K interaction in the cytosol. Plays a role in E2-mediated cell cycle progression by interacting with RB1. May have important functional implications in ER/growth factor cross-talk. Interacts with several growth factor signaling components including EGFR and HRS. Functions as the key stabilizing component of the Five Friends of Methylated CHTOP (5FMC) complex; the 5FMC complex is recruited to ZNF148 by methylated CHTOP, leading to desumoylation of ZNF148 and subsequent transactivation of ZNF148 target genes. Component of the PELP1 complex involved in the nucleolar steps of 28S rRNA maturation and the subsequent nucleoplasmic transit of the pre-60S ribosomal subunit. Regulates pre-60S association of the critical remodeling factor MDN1 (PubMed:21326211). May promote tumorigenesis via its interaction with and modulation of several oncogenes including SRC, PI3K, STAT3 and EGFR. Plays a role in cancer cell metastasis via its ability to modulate E2-mediated cytoskeleton changes and cell migration via its interaction with SRC and PI3K","subcellular_location":"Nucleus, nucleolus; Nucleus, nucleoplasm; Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8IZL8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PELP1","classification":"Common Essential","n_dependent_lines":1173,"n_total_lines":1208,"dependency_fraction":0.9710264900662252},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALM3","stoichiometry":0.2},{"gene":"METAP2","stoichiometry":0.2},{"gene":"RACK1","stoichiometry":0.2},{"gene":"SRP68","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PELP1","total_profiled":1310},"omim":[{"mim_id":"620291","title":"WD REPEAT-CONTAINING PROTEIN 18; WDR18","url":"https://www.omim.org/entry/620291"},{"mim_id":"618738","title":"TUBULIN TYROSINE LIGASE-LIKE 4; TTLL4","url":"https://www.omim.org/entry/618738"},{"mim_id":"617259","title":"DDB1- AND CUL4-ASSOCIATED FACTOR 1; DCAF1","url":"https://www.omim.org/entry/617259"},{"mim_id":"616717","title":"TESTIS-EXPRESSED GENE 10; TEX10","url":"https://www.omim.org/entry/616717"},{"mim_id":"609455","title":"PROLINE-, GLUTAMIC ACID-, AND LEUCINE-RICH PROTEIN 1; PELP1","url":"https://www.omim.org/entry/609455"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Nucleoli","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PELP1"},"hgnc":{"alias_symbol":["MNAR"],"prev_symbol":[]},"alphafold":{"accession":"Q8IZL8","domains":[{"cath_id":"1.25.40","chopping":"84-210","consensus_level":"medium","plddt":88.8076,"start":84,"end":210},{"cath_id":"1.25.40","chopping":"411-471_515-633","consensus_level":"medium","plddt":85.563,"start":411,"end":633},{"cath_id":"1.20.5","chopping":"899-940","consensus_level":"medium","plddt":78.276,"start":899,"end":940}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IZL8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IZL8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IZL8-F1-predicted_aligned_error_v6.png","plddt_mean":63.16},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PELP1","jax_strain_url":"https://www.jax.org/strain/search?query=PELP1"},"sequence":{"accession":"Q8IZL8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IZL8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IZL8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IZL8"}},"corpus_meta":[{"pmid":"30771436","id":"PMC_30771436","title":"Metformin 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It physically interacts with ERα and with general transcriptional coactivators p300 and CBP, and enhances 17β-estradiol-dependent transcriptional activation from estrogen response elements in a dose-dependent manner. PELP1 contains nine NR-interacting LXXLL motifs, a zinc finger, and glutamic acid- and proline-rich regions.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene assays (ERE-luciferase), Western blotting, tissue expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, reporter assays, and domain characterization; foundational cloning paper independently replicated across many subsequent studies\",\n      \"pmids\": [\"11481323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MNAR/PELP1 acts as a scaffold protein mediating ERα-Src interaction: MNAR interacts with the SH3 domain of cSrc via its N-terminal PXXP motif, and with ERα via two N-terminal LXXLL motifs. Mutation of the PXXP motif abolished MNAR-induced Src activation and ER transcriptional stimulation. ERα interacts with Src's SH2 domain via phosphotyrosine 537, and this complex is further stabilized by MNAR-ER interaction. Mutation of LXXLL motifs prevented ER-MNAR complex formation and eliminated Src/MAPK pathway activation.\",\n      \"method\": \"Mutational analysis of MNAR and ERα, co-immunoprecipitation, functional kinase activation assays, reporter gene assays\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — structure-function mutagenesis of key motifs combined with functional readouts, independently replicated in subsequent studies\",\n      \"pmids\": [\"14963108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PELP1 physically associates with retinoblastoma protein (pRb) via pRb's C-terminal pocket domain. PELP1 overexpression leads to persistent hyperphosphorylation of pRb at Ser-807/Ser-811 in an E2-dependent manner, enhances progression to S phase, and potentiates cyclin D1 expression. PELP1/pRb interaction is required for maximal PELP1 coactivation function and is modulated by antiestrogen agents.\",\n      \"method\": \"Co-immunoprecipitation, stable overexpression in MCF-7 cells, phospho-specific pRb antibodies, flow cytometry, reporter gene assays with mutant pRb cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, domain mapping, mutant cell lines, multiple orthogonal methods in one study\",\n      \"pmids\": [\"12682072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PELP1 localizes to the nucleus, associates with chromatin and nuclear matrix fractions, and is recruited to 17β-estradiol-responsive promoters upon ligand stimulation. PELP1 interacts with histones H1 and H3 (with preference for H1) via its C-terminal region. PELP1 overexpression increases histone acetyltransferase activity and micrococcal nuclease sensitivity of ERE-containing nucleosomes. A PELP1 mutant lacking the H1-binding domain acts as a dominant negative, blocking ERα-mediated transcription. PELP1 displays cyclic association and dissociation from promoters in opposite phase to histone H1, suggesting a role in chromatin remodeling via H1 displacement.\",\n      \"method\": \"Subnuclear fractionation, confocal microscopy, ChIP, far Western analysis, deletion analysis, histone acetyltransferase enzymatic assay, micrococcal nuclease sensitivity assay, dominant-negative mutant studies\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including enzymatic assays, far Western, ChIP, and functional dominant-negative validation in one study\",\n      \"pmids\": [\"15374949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PELP1 functions as a corepressor of multiple nuclear receptors and non-NR transcription factors (GR, Nur77, AP1, NF-κB, TCF/SRF) in the absence of ER. The N-terminal leucine-abundant region of PELP1 interacts with HDAC2 and exhibits repressive activity when tethered to chromatin. The C-terminal glutamic acid-abundant region binds hypoacetylated histones H3 and H4, preventing their acetylation. ER binding reverses PELP1's role to promote histone hyperacetylation.\",\n      \"method\": \"Reporter gene assays, co-immunoprecipitation, domain mapping, chromatin tethering assays, cell proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping with co-IP and functional reporter assays using multiple NR/transcription factor contexts\",\n      \"pmids\": [\"15456770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Cytoplasmic localization of PELP1 (PELP1-cyto mutant) confers hypersensitivity to estrogen, resistance to tamoxifen, and tumorigenicity in nude mice. Cytoplasmic PELP1 shows increased association with Src, enhanced MAPK activation, constitutive AKT activation, and interaction with the p85 subunit of PI3K leading to PI3K activation. Cytoplasmic PELP1 also interacts with EGFR and participates in growth factor-mediated ER transactivation.\",\n      \"method\": \"Engineered cytoplasm-restricted PELP1 mutant, stable MCF-7 cell lines, xenograft tumor assays, co-immunoprecipitation, kinase activation assays, Western blotting\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — engineered localization mutant with multiple functional and biochemical readouts, in vivo xenograft validation\",\n      \"pmids\": [\"16140940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HRS (hepatocyte growth factor-regulated tyrosine kinase substrate) is a novel PELP1-binding protein identified by yeast two-hybrid screen. HRS sequesters PELP1 in the cytoplasm and inhibits PELP1 coactivation of ER transcription. HRS-PELP1 interaction activates MAPK in an EGFR-dependent but ER/Src/Shc-independent manner.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, subcellular fractionation, reporter gene assays, MAPK activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus functional assays, single lab\",\n      \"pmids\": [\"16352611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MNAR/PELP1 regulates androgen receptor (AR)-mediated nongenomic signaling. MNAR and AR co-immunoprecipitate via the LXXLL-rich segment of MNAR and the ligand binding domain of AR. MNAR also interacts with Gβ via the same region. Reduction of MNAR expression by RNAi in Xenopus oocytes enhances testosterone-triggered meiosis and MAPK activation, and decreases Gβγ-mediated signaling, implicating MNAR in maintaining meiotic arrest.\",\n      \"method\": \"RNA interference in Xenopus oocytes, co-immunoprecipitation, transient transfection reporter assays\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus RNAi functional readout in Xenopus physiological model, single lab\",\n      \"pmids\": [\"15831520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MNAR/PELP1 phosphorylation at Tyr-920 by cSrc is required for interaction with p85 (PI3K regulatory subunit) and E2-induced activation of the PI3K/Akt pathway. Mutation Y920A abolishes MNAR-p85 interaction and PI3K/Akt activation (abrogating E2-induced protection from apoptosis) but does not impair Src/MAPK pathway activation or cell proliferation. Endogenous MNAR, ERα, cSrc, and p85 form a complex in E2-treated MCF-7 cells.\",\n      \"method\": \"Site-directed mutagenesis, co-immunoprecipitation, in vitro kinase assays, reporter gene assays, cell viability/apoptosis assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis with multiple functional readouts, biochemical reconstitution of the pathway, single lab\",\n      \"pmids\": [\"17194752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PELP1 functions as a coactivator of RXRα, physically interacting with RXRα both in vitro and in vivo. PELP1 promotes formation and stability of RXRα homodimers on consensus oligonucleotides and enhances RXRα-mediated transcription and apoptosis in response to 9-cis-retinoic acid. PELP1 also coactivates RXRα-PPARγ heterodimers.\",\n      \"method\": \"Co-immunoprecipitation, EMSA supershift assays, reporter gene assays, stable MCF-7 overexpression, siRNA knockdown, differentiation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo binding plus functional assays, single lab\",\n      \"pmids\": [\"16574651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PELP1 localizes to autophagosomes in cancer cells treated with resveratrol. The intermediary molecule for PELP1 accumulation in autophagosomes is HRS. Both PELP1 and HRS relocalize to autophagosomes (marked by GFP-LC3) upon resveratrol treatment.\",\n      \"method\": \"Confocal microscopy, GFP-LC3 autophagic marker, pharmacological autophagy inhibitors (3-methyladenine)\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — live imaging co-localization with autophagic marker plus pharmacological controls, single lab\",\n      \"pmids\": [\"17804729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PELP1 is recruited to the BCAS3 chromatin locus and activates BCAS3 expression; BCAS3 in turn functions as an ERα coactivator that requires PELP1 to enhance ER transactivation activity. BCAS3 physically associates with histone H3 and P/CAF and possesses histone acetyltransferase activity.\",\n      \"method\": \"ChIP assays, reporter gene assays, co-immunoprecipitation, siRNA knockdown, stable overexpression\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, co-IP, and functional reporter assays with multiple lines of evidence, single lab\",\n      \"pmids\": [\"17505058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MNAR/PELP1 interacts with GR in the nucleus (but not cytoplasm) and modulates GR transactivation in a cell-type and concentration-dependent manner: MNAR inhibits GR AF1 (ligand-independent) but potentiates AF2 (ligand-dependent). The region MNAR 884-1130 and the N-terminal 1-400 domain (containing LXXLL motifs) both independently inhibit GR transactivation. This GR regulatory function is independent of c-Src activity.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene assays, deletion analysis, c-Src inhibitors and knockdown, immunofluorescence\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain deletion mapping with co-IP and reporter assays in multiple cell lines, c-Src independence demonstrated, single lab\",\n      \"pmids\": [\"18682536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Growth factor signaling promotes phosphorylation of PELP1 via protein kinase A (PKA). PKA directly phosphorylates PELP1 in vitro; mutation of the putative PKA site in PELP1 compromises growth factor-induced ER transactivation, subnuclear localization of PELP1, and PELP1-mediated coactivation function.\",\n      \"method\": \"In vivo phosphorylation labeling, phospho-substrate specific antibodies, PKA inhibitor (H89), in vitro kinase assays with purified PKA, deletion and site-directed mutagenesis, reporter gene assays\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus mutagenesis plus functional validation, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"18505929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PELP1 deregulation contributes to increased aromatase expression via activation of aromatase promoter I.3/II. PELP1 is recruited to the aromatase I.3/II promoter as shown by ChIP. PELP1-mediated aromatase induction requires functional Src and PI3K pathways and involves interaction with orphan receptor ERRα and histone demethylases. HER2 signaling enhances PELP1 recruitment to the aromatase promoter.\",\n      \"method\": \"ChIP assays, reporter gene assays, aromatase activity assays, Western blotting, xenograft and transgenic mouse models\",\n      \"journal\": \"The Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-based promoter recruitment plus functional signaling pathway requirements, in vivo confirmation, single lab\",\n      \"pmids\": [\"19800002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PELP1 is a reader of histone H3 methylation marks. PELP1 interacts with the histone lysine demethylase KDM1 (LSD1). Both are co-recruited to ERα target genes. PELP1 depletion affects dimethyl histone modifications (H3K4me2 and H3K9me2) at ERα target genes. PELP1 alters KDM1 substrate specificity from H3K4 to H3K9 dimethylation. Effective demethylation of H3K9me2 requires a KDM1-ERα-PELP1 functional complex.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assays, siRNA knockdown, in vitro demethylase activity assays, reporter gene assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — enzymatic substrate specificity demonstrated in vitro plus ChIP in vivo, PELP1 identified as histone mark reader, multiple orthogonal methods\",\n      \"pmids\": [\"20448663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TTLL4 polyglutamylase modifies PELP1 by adding glutamate side chains (polyglutamylation) to PELP1's glutamate stretch region. PELP1 polyglutamylation influences PELP1 interaction with histone H3 and affects histone H3 acetylation. PELP1 interacts with LAS1L and SENP3, components of the MLL1-WDR5 supercomplex involved in chromatin remodeling.\",\n      \"method\": \"Knockdown of TTLL4 by shRNA, immunoprecipitation, co-immunoprecipitation, cell growth assays, correlation of TTLL4 expression with PELP1 polyglutamylation levels\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — identification of novel PTM with biochemical consequences for histone interaction, complex membership identified, single lab\",\n      \"pmids\": [\"20442285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PELP1 is a novel substrate of cyclin-dependent kinases (CDKs). Ser477 and Ser991 of PELP1 are CDK phosphorylation sites identified by site-directed mutagenesis and in vitro kinase assays. PELP1 is hyperphosphorylated during cell cycle progression. PELP1 CDK-site mutants exhibit defects in E2-mediated cell cycle progression and oncogenic functions in vivo. PELP1 modulates E2F1 transactivation and is recruited to pRb/E2F target gene promoters, facilitating ER-cell cycle machinery crosstalk.\",\n      \"method\": \"Site-directed mutagenesis, in vitro CDK kinase assays, phospho-specific antibody, ChIP assays, reporter gene assays, stable cell lines, xenograft models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, ChIP, and in vivo functional validation, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"20807815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PELP1 localizes to the nucleolus and is associated with active ribosomal RNA transcription. PELP1 nucleolar localization is cell-cycle dependent (highest in S and G2 phases) and regulated by CDK activity. PELP1 depletion decreases pre-rRNA expression. PELP1 is recruited to the promoter regions of rDNA (ChIP) and is needed for optimal rDNA transcription. PELP1 domains required for nucleolar localization are essential for rDNA reporter activation.\",\n      \"method\": \"Pharmacological inhibitors, confocal microscopy, cell synchronization, CDK site mutants, siRNA, reporter gene assays (rDNA-luciferase), ChIP assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by microscopy linked to functional consequence via ChIP and reporter assays, siRNA knockdown, multiple orthogonal methods\",\n      \"pmids\": [\"21695158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PELP1 forms a protein complex with AR, ERβ, and PELP1 on AR-responsive DNA elements in prostate cancer cells in response to E2. This complex enables E2-induced transcription of AR-responsive genes and E2-stimulated cell proliferation. Knockdown of PELP1, AR, or ERβ blocks complex assembly, blocks E2-induced AR gene activation, and blocks proliferation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assays, siRNA knockdown, reporter gene assays, cell proliferation assays\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and co-IP demonstrate complex on DNA, functional siRNA knockdown, single lab\",\n      \"pmids\": [\"22403175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PELP1 binds to the promoters of miR-200a and miR-141 and represses their expression by recruiting histone deacetylase 2 (HDAC2). PELP1 knockdown reduced ZEB1 and ZEB2 expression and metastatic potential. Re-introduction of miR-200a and miR-141 mimetics reversed PELP1 target gene expression and reduced PELP1-driven migration/invasion in vitro and in vivo.\",\n      \"method\": \"ChIP assays, whole genome miR array, siRNA knockdown, HDAC inhibitor assays, Boyden chamber assays, xenograft tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-based promoter recruitment, pharmacological inhibition, genetic rescue with miR mimetics, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"23975430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PELP1 is a reader of histone arginine methyl modifications. PELP1 functionally interacts with the arginine methyltransferase CARM1; their interaction is enhanced by ERα. PELP1-CARM1 interactions synergistically enhance ERα transactivation. PELP1 alters histone H3 arginine methylation status at ERα target gene promoters as shown by ChIP. PELP1 knockdown decreases CARM1-driven arginine dimethylation in vivo.\",\n      \"method\": \"Histone peptide array, co-immunoprecipitation, ChIP assays, pharmacological CARM1 inhibition, siRNA knockdown, reporter gene assays, xenograft models\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — histone peptide array binding, co-IP, ChIP, functional reporter assays with pharmacological and genetic inhibition, in vivo confirmation, single lab\",\n      \"pmids\": [\"23486015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PELP1 interacts with the arginine methyltransferase PRMT6 and modifies PRMT6 functions. PELP1 and PRMT6 are co-recruited to ERα target genes; PELP1 knockdown affects enrichment of histone H3R2 dimethylation. PELP1 co-localizes with splicing factor SC35 at nuclear speckles and participates in alternative splicing, binding RNA with preference for poly-C sequences.\",\n      \"method\": \"RNA-sequencing, co-immunoprecipitation, ChIP assays, RNA binding assays, immunofluorescence co-localization, siRNA knockdown, reporter gene assays\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, and RNA binding demonstrated, single lab with multiple methods\",\n      \"pmids\": [\"24447537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PELP1 serves as a scaffold for ER/PR/PELP1/IGF1R-containing transcription complexes in breast cancer cells. Unliganded PR-B enhances estradiol-responsive ER transcription via scaffolding these complexes on ERE-containing promoters. The ER/PR/PELP1 complex was also detected in human breast cancer samples.\",\n      \"method\": \"ChIP assays, co-immunoprecipitation, stable cell line expression, growth assays, microarray gene expression, immunoprecipitation from patient tumor samples\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus co-IP in cell lines plus patient tumor confirmation, single lab\",\n      \"pmids\": [\"24469035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PELP1 cross-talks with the mTOR signaling pathway. PELP1 knockdown reduces activation of mTOR downstream signaling components. PELP1 overexpression excessively activates mTOR signaling. mTOR signaling complex proteins are detected in PELP1 immunoprecipitates.\",\n      \"method\": \"Co-immunoprecipitation, Western blotting (phospho-mTOR pathway markers), siRNA knockdown, xenograft tumor models, mTOR inhibitor treatment\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single co-IP plus functional pharmacological evidence, in vivo validation, single lab\",\n      \"pmids\": [\"24688046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PELP1 interacts with mutant p53 (MTp53), regulates its recruitment to target gene promoters, and alters epigenetic marks at those promoters. PELP1 knockdown reduces MTp53 target gene expression and increases apoptosis upon genotoxic stress. PELP1 regulates E2F1 stability in a KDM1A-dependent manner. PELP1 phosphorylation at S1033 plays an important role in its oncogenic functions in TNBC cells.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assays, siRNA knockdown, reporter gene assays, flow cytometry\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, and functional readouts with phospho-mutant, single lab\",\n      \"pmids\": [\"25788226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PELP1 interacts with glucocorticoid receptor (GR) and is induced in a HIF-dependent manner in response to hypoxia or dexamethasone. PELP1 is part of a phospho-GR/HIF/PELP1 complex that assembles on the BRK promoter, promoting Brk expression in triple-negative breast cancer.\",\n      \"method\": \"ChIP assays, co-immunoprecipitation, Western blotting, GR ligand treatments, hypoxia conditions, siRNA knockdown\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-based promoter occupancy plus co-IP for complex formation, single lab\",\n      \"pmids\": [\"26825173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cytoplasmic localization of PELP1 up-regulates IKKε and increases phosphorylation of the NF-κB subunit RelB. PELP1-cyto-expressing mammary epithelial cells secrete factors that activate macrophages in a paracrine manner, and those activated macrophages produce conditioned medium that drives HMEC migration. This migration is reduced by IKKε shRNA knockdown.\",\n      \"method\": \"Gene expression analysis, Western blotting, conditioned medium experiments, shRNA knockdown, Boyden chamber migration assays, PELP1-cyto mutant cell lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — engineered PELP1-cyto mutant, paracrine assay, IKKε genetic knockdown confirms pathway, single lab\",\n      \"pmids\": [\"27881676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cytoplasmic PELP1 forms a complex with AIB1/SRC-3, identified as a novel binding partner. Cytoplasmic PELP1 expression elevates basal phosphorylation (Thr24 activation) of AIB1, enhances ALDH+ tumorsphere formation, and upregulates specific target genes independently of hormone stimulation. Direct AIB1 knockdown or pharmacological inhibition (SI-2) abrogates cytoplasmic PELP1-induced tumorsphere formation.\",\n      \"method\": \"Co-immunoprecipitation, tumorsphere assays (ALDH+ sorting), shRNA knockdown, Western blotting, syngeneic in vivo tumor studies\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional genetic and pharmacological inhibition, in vivo confirmation, single lab\",\n      \"pmids\": [\"29348189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cytoplasmic complexes of PELP1 and SRC-3 modulate breast cancer stem cell expansion through upregulation of HIF-activated metabolic target genes PFKFB3 and PFKFB4. PELP1 physically interacts with PFKFB3 and PFKFB4 proteins. Inhibition of PFKFB3/4 kinase activity blocks PELP1-induced tumorsphere formation and PELP1/SRC-3 protein-protein interactions. Cytoplasmic PELP1 increases both glycolysis and mitochondrial respiration as measured by Seahorse metabolic assays.\",\n      \"method\": \"Co-immunoprecipitation, Seahorse metabolic assays, tumorsphere assays, PFKFB inhibitors, shRNA knockdown, xenograft and patient-derived organoid models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus Seahorse functional metabolic readout plus genetic and pharmacological inhibition, single lab\",\n      \"pmids\": [\"34103681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PELP1 interacts with TFAP2C (transcription factor AP-2γ). PELP1 functions as a coactivator of TFAP2C and mediates TFAP2C-induced changes in histone methylation at the RET promoter, increasing RET expression and downstream AKT and ERK pathway activation. PELP1 knockdown abrogates TFAP2C-driven breast cancer progression in vivo.\",\n      \"method\": \"Co-immunoprecipitation, RNA-seq, ChIP assays, reporter gene assays, siRNA knockdown, Western blotting, xenograft models\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, functional reporter assays, and in vivo xenograft validation, single lab\",\n      \"pmids\": [\"33269540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PELP1 is the central scaffold for the human Rix1 complex, whose members include WDR18, TEX10, and SENP3. The cryo-EM structure of the PELP1 Rix1 domain–WDR18 subcomplex was determined at 2.7 Å, revealing an interconnected tetrameric assembly and the architecture of PELP1's eleven LxxLL motifs, none of which are in a conformation that would support steroid receptor binding within this complex. Association with WDR18 may direct PELP1 activity away from SR coactivation.\",\n      \"method\": \"Cryo-EM structure determination (2.7 Å), in vitro reconstitution of mammalian Rix1 complex, identification of stable sub-complex\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure with in vitro reconstitution; directly resolves LxxLL motif architecture and demonstrates incompatibility with SR binding in this complex context\",\n      \"pmids\": [\"36351913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SETDB1 interacts with PELP1, identified initially by yeast two-hybrid screen and confirmed by co-immunoprecipitation and GST pull-down. PELP1 is necessary for SETDB1-mediated Akt methylation and phosphorylation. SETDB1 overexpression promotes tamoxifen resistance in breast cancer cells, and PELP1 knockdown abolishes these effects.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, GST pull-down, in vitro methylation assays, Western blotting, xenograft models\",\n      \"journal\": \"Breast cancer research : BCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast two-hybrid plus GST pull-down plus co-IP plus in vitro methylation assay plus in vivo xenograft, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"35395812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SMIP34, a small-molecule inhibitor of PELP1, directly binds to PELP1 and induces its degradation via the proteasome pathway. SMIP34 inhibits PELP1 oncogenic functions including extranuclear signaling (ERK, mTOR, S6, 4EBP1), ribosomal biogenesis functions (cMyc, LAS1L, TEX10, SENP3/Rix complex), and suppresses ER+ breast cancer progression in cell line-derived and patient-derived xenografts.\",\n      \"method\": \"Yeast two-hybrid screen for PELP1 peptide inhibitors, biochemical binding assays, computational modeling, RNA-seq, Western blotting, xenograft and PDX models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding assay, mechanism of action (proteasome degradation), RNA-seq pathway analysis, and in vivo xenograft and PDX validation, multiple orthogonal methods\",\n      \"pmids\": [\"35950923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PELP1 serves as the central scaffold of the rixosome complex upon which enzymatic subunits modularly assemble. The C-terminal proline-rich IDR of PELP1 mediates association with the AAA-ATPase MDN1, histones, and SENP3. The glutamic acid-rich region of the PELP1 IDR can chaperone the histone octamer in vitro. An X-ray crystal structure of a short linear motif (SLiM) from the PELP1 IDR bound to SENP3 reveals how PELP1 allosterically activates SUMO protease activity.\",\n      \"method\": \"X-ray crystallography (SLiM-SENP3 structure), in vitro histone octamer chaperoning assay, biochemical reconstitution of rixosome subunit assembly, structural and functional domain analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — X-ray structure plus in vitro reconstitution plus enzymatic (SUMO protease) activation assay, multiple orthogonal methods, single recent paper\",\n      \"pmids\": [\"40712028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PELP1 promotes glioblastoma progression by interacting with and functioning as a coactivator of β-catenin, activating Wnt/β-catenin target gene expression. PELP1 knockdown significantly reduced expression of Wnt/β-catenin pathway genes and improved survival of orthotopic GBM tumor-bearing mice.\",\n      \"method\": \"Co-immunoprecipitation, RNA-seq, reporter gene assays, siRNA knockdown, orthotopic mouse models\",\n      \"journal\": \"Neuro-oncology advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus reporter assays plus in vivo validation, single lab\",\n      \"pmids\": [\"32309805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PELP1 interacts with FHL2 to potentiate transcriptional activation of downstream target genes including CCND1, CCND2, CDK6, ANG, CCL2, and MMP3 in ectopic endometrial stromal cells. PELP1 knockdown inhibited proliferation, angiogenesis, and inflammation in endometriosis models.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, animal models, qRT-PCR, Western blotting\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP study, limited mechanistic follow-up, single lab\",\n      \"pmids\": [\"41165240\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PELP1 is a large multidomain scaffold protein and proto-oncogene that functions as a coregulator of estrogen receptor alpha (ERα) and multiple other nuclear receptors by: (1) serving as the central scaffold of the rixosome/Rix1 complex (with WDR18, TEX10, SENP3) for ribosome biogenesis and RNA decay, allosterically activating SENP3 SUMO protease activity; (2) reading histone H3 methylation marks (H3K4me2, H3K9me2, arginine methylation) and altering the substrate specificity of KDM1 (LSD1) from H3K4 to H3K9 while recruiting HDAC2 and CARM1 to modulate epigenetic states at ERα target gene promoters; (3) scaffolding rapid non-genomic ER signaling by bridging ERα (via LXXLL motifs) and cSrc (via PXXP/SH3 domain interaction), with subsequent MNAR phosphorylation at Tyr920 by cSrc enabling p85/PI3K recruitment and Akt activation; (4) interacting with pRb, E2F1, and CDKs (phosphorylated at Ser477/Ser991) to regulate cell cycle progression; and (5) acting in the cytoplasm to activate mTOR, MAPK/Src, and metabolic (PFKFB3/4) pathways that drive therapy resistance and cancer stem cell expansion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PELP1 is a large multidomain scaffold protein that functions both as a nuclear receptor coregulator and as the structural core of a ribosome biogenesis complex, integrating hormone signaling, chromatin modification, and cell cycle control to drive proliferation [#0, #15, #31]. It was first identified as an estrogen receptor alpha (ERα) coactivator that binds ERα through its nine LXXLL motifs and recruits the general coactivators p300/CBP to enhance estradiol-dependent transcription [#0]. PELP1 reads histone methylation marks and remodels chromatin at ERα target promoters: it interacts with histones H1 and H3, displaces H1 in cyclic phase with promoter occupancy, and reprograms the demethylase KDM1/LSD1 to switch its substrate specificity from H3K4 to H3K9 while engaging the arginine methyltransferases CARM1 and PRMT6 [#3, #15, #21, #22]. Its transcriptional output is context-dependent — acting as a corepressor in the absence of ER by recruiting HDAC2 to bind hypoacetylated histones, and switching to coactivation upon ER binding [#4]. Beyond the nucleus, PELP1 serves as a scaffold for rapid non-genomic signaling, bridging ERα via LXXLL motifs and cSrc via an N-terminal PXXP motif to activate Src/MAPK, and after cSrc phosphorylates it at Tyr920 it recruits the p85 subunit of PI3K to drive Akt activation [#1, #8]. Cytoplasmic restriction of PELP1 confers estrogen hypersensitivity, tamoxifen resistance, and tumorigenicity through constitutive Src/MAPK, PI3K/Akt, mTOR, and metabolic (PFKFB3/4) signaling and cancer stem cell expansion [#5, #24, #29]. PELP1 is a CDK substrate (Ser477/Ser991) that couples ER signaling to the pRb/E2F cell cycle machinery and to rDNA transcription in the nucleolus [#2, #17, #18]. Structurally, PELP1 is the central scaffold of the human Rix1/rixosome complex with WDR18, TEX10, and SENP3, where its proline- and glutamate-rich intrinsically disordered region chaperones histones and allosterically activates SENP3 SUMO protease activity [#31, #34]. PELP1's coregulator and scaffolding functions extend to other nuclear receptors (AR, RXRα, GR) and transcription factors (β-catenin, TFAP2C), and it is a validated therapeutic target whose small-molecule inhibitor SMIP34 induces its proteasomal degradation [#7, #9, #30, #33, #35].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established PELP1's founding identity by showing it physically binds ERα and the p300/CBP coactivators to amplify estrogen-responsive transcription, defining it as a nuclear receptor coregulator.\",\n      \"evidence\": \"Co-IP, ERE-luciferase reporter assays, and domain mapping identifying nine LXXLL motifs\",\n      \"pmids\": [\"11481323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which LXXLL motifs mediate binding\", \"No structural basis for coactivation\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved how PELP1 scaffolds non-genomic ER signaling, showing it bridges cSrc (via PXXP) and ERα (via LXXLL) to activate Src/MAPK, extending its role beyond transcription into membrane-proximal kinase activation.\",\n      \"evidence\": \"Motif mutagenesis, co-IP, and kinase/reporter assays in mammalian cells\",\n      \"pmids\": [\"14963108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define downstream PI3K branch\", \"Phosphorylation events not yet mapped\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected PELP1 to cell cycle control by showing it binds pRb and promotes its hyperphosphorylation and S-phase entry, linking ER coactivation to proliferative machinery.\",\n      \"evidence\": \"Co-IP, phospho-pRb antibodies, flow cytometry in MCF-7 cells\",\n      \"pmids\": [\"12682072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for pRb phosphorylation not defined here\", \"Direct vs indirect effect unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined PELP1's chromatin-remodeling mechanism, showing it binds histones H1/H3, displaces H1 cyclically at promoters, and can act as either coactivator or corepressor via distinct domains binding HDAC2 or hypoacetylated histones.\",\n      \"evidence\": \"Subnuclear fractionation, ChIP, far Western, HAT assays, MNase sensitivity, dominant-negative and tethering assays\",\n      \"pmids\": [\"15374949\", \"15456770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Histone-mark readers not yet identified\", \"Switch mechanism between repression and activation incompletely defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated that cytoplasmic PELP1 localization is a driver of therapy resistance and tumorigenicity through constitutive Src, MAPK, AKT, and PI3K activation, mechanistically linking subcellular distribution to oncogenic phenotype.\",\n      \"evidence\": \"Engineered cytoplasm-restricted mutant, xenografts, co-IP, kinase assays\",\n      \"pmids\": [\"16140940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous determinants of PELP1 localization unknown\", \"Did not define molecular trigger for cytoplasmic accumulation\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Broadened PELP1's coregulator scope to other steroid receptors and identified cytoplasmic regulators, showing AR/Gβ engagement governs meiotic arrest and HRS sequesters PELP1 in the cytoplasm to restrain ER coactivation.\",\n      \"evidence\": \"Yeast two-hybrid, RNAi in Xenopus oocytes, co-IP, fractionation, reporter assays\",\n      \"pmids\": [\"15831520\", \"16352611\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings\", \"Physiological relevance of HRS sequestration in human cancer not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Pinpointed the molecular switch for the PI3K/Akt arm, showing cSrc phosphorylation of PELP1 at Tyr920 is required for p85 recruitment and E2-induced Akt-mediated survival, separating this branch from Src/MAPK and proliferation.\",\n      \"evidence\": \"Site-directed Y920A mutagenesis, co-IP, in vitro kinase, apoptosis assays\",\n      \"pmids\": [\"17194752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other phosphosites not yet characterized\", \"Single-lab reconstitution\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended PELP1 coactivation to RXRα signaling, showing it stabilizes RXRα homodimers and RXRα-PPARγ heterodimers and enhances retinoid-induced transcription and apoptosis.\",\n      \"evidence\": \"Co-IP, EMSA supershift, reporter and differentiation assays\",\n      \"pmids\": [\"16574651\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"In vivo retinoid relevance not established\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed PELP1 is integrated into growth factor signaling through PKA phosphorylation that controls its subnuclear localization and coactivation, and clarified that its GR regulation is c-Src-independent and domain-specific.\",\n      \"evidence\": \"In vitro PKA kinase assays, phospho-mutants, H89 inhibitor, deletion mapping, reporter assays\",\n      \"pmids\": [\"18505929\", \"18682536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PKA site sequence not fully defined\", \"Cell-type dependence of GR effects unexplained\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked PELP1 to estrogen biosynthesis by showing it is recruited to the aromatase I.3/II promoter via ERRα and histone demethylases to upregulate aromatase, with HER2 enhancing recruitment.\",\n      \"evidence\": \"ChIP, aromatase activity and reporter assays, xenograft and transgenic models\",\n      \"pmids\": [\"19800002\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct ERRα-PELP1 contacts not mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified PELP1 as a histone-mark reader that reprograms KDM1/LSD1 substrate specificity from H3K4 to H3K9, providing a mechanistic basis for its bidirectional chromatin effects at ER target genes.\",\n      \"evidence\": \"Co-IP, ChIP, siRNA, in vitro demethylase assays\",\n      \"pmids\": [\"20448663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of specificity switch unresolved\", \"Genome-wide scope not mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Coupled PELP1 to cell cycle and nucleolar function, showing CDKs phosphorylate Ser477/Ser991 to regulate E2-driven proliferation, E2F1 transactivation, and cell-cycle-dependent nucleolar rDNA transcription.\",\n      \"evidence\": \"In vitro CDK kinase assays, phospho-mutants, ChIP, cell synchronization, rDNA reporter assays, xenografts\",\n      \"pmids\": [\"20807815\", \"21695158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CDK phosphorylation directs nucleolar targeting not fully mechanistic\", \"Link to ribosome biogenesis complex not yet made\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed a PTM regulating PELP1 chromatin function — TTLL4-mediated polyglutamylation of its glutamate stretch — and first placed PELP1 in chromatin-remodeling complexes with LAS1L and SENP3.\",\n      \"evidence\": \"shRNA knockdown of TTLL4, immunoprecipitation, co-IP, growth assays\",\n      \"pmids\": [\"20442285\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of complex membership not resolved here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Expanded PELP1's epigenetic reader/writer activity to arginine methylation (CARM1, PRMT6) and to RNA-level regulation, showing it controls H3 arginine methylation at ER targets, localizes to nuclear speckles with SC35, and participates in alternative splicing.\",\n      \"evidence\": \"Histone peptide arrays, RNA-seq, co-IP, ChIP, RNA-binding assays, xenografts\",\n      \"pmids\": [\"23486015\", \"24447537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA-binding specificity beyond poly-C undefined\", \"Splicing program targets incompletely mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established PELP1 as a driver of metastasis through epigenetic repression, showing it recruits HDAC2 to silence miR-200a/miR-141, derepressing ZEB1/ZEB2 to promote EMT and invasion.\",\n      \"evidence\": \"ChIP, miR array, HDAC inhibitors, miR mimetic rescue, Boyden chamber, xenografts\",\n      \"pmids\": [\"23975430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PELP1 promoter-binding mode unresolved\", \"Other miRNA targets not surveyed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed PELP1 scaffolds multi-receptor transcription complexes (ER/PR/IGF1R) and cross-talks with mTOR, integrating hormone and growth-factor pathways to support proliferation.\",\n      \"evidence\": \"ChIP, co-IP, microarray, patient tumor IP, mTOR inhibitor treatment, xenografts\",\n      \"pmids\": [\"24469035\", \"24688046\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs scaffolded mTOR contacts unclear\", \"Single-lab co-IP for mTOR association\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected PELP1 to mutant-p53 and TNBC oncogenic programs, showing it regulates MTp53 promoter recruitment and E2F1 stability in a KDM1A-dependent manner, with S1033 phosphorylation important for oncogenic function.\",\n      \"evidence\": \"Co-IP, ChIP, siRNA, reporter assays, flow cytometry\",\n      \"pmids\": [\"25788226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"S1033 kinase not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined hypoxia- and glucocorticoid-responsive and inflammatory roles, showing PELP1 assembles a phospho-GR/HIF complex to induce Brk, and cytoplasmic PELP1 drives IKKε/RelB-mediated paracrine macrophage activation and migration.\",\n      \"evidence\": \"ChIP, co-IP, hypoxia/dexamethasone treatments, conditioned-medium and migration assays, shRNA\",\n      \"pmids\": [\"26825173\", \"27881676\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PELP1-HIF contacts not mapped\", \"Secreted paracrine factors not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified the cytoplasmic PELP1-AIB1/SRC-3 axis as a driver of cancer stem cell expansion, showing PELP1 elevates AIB1 Thr24 phosphorylation and ALDH+ tumorsphere formation independently of hormone.\",\n      \"evidence\": \"Co-IP, tumorsphere/ALDH sorting, SI-2 inhibition, shRNA, syngeneic models\",\n      \"pmids\": [\"29348189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of AIB1 activation by PELP1 undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked the PELP1/SRC-3 cytoplasmic complex to metabolic reprogramming, showing PELP1 binds PFKFB3/PFKFB4 and increases glycolysis and respiration to sustain stem cell expansion.\",\n      \"evidence\": \"Co-IP, Seahorse assays, PFKFB inhibitors, tumorspheres, xenograft and organoid models\",\n      \"pmids\": [\"34103681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PELP1 directly regulates PFKFB kinase activity unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Generalized PELP1 coactivation beyond nuclear receptors to lineage transcription factors, showing it coactivates TFAP2C and β-catenin to drive RET/AKT/ERK signaling and Wnt target gene expression in breast cancer and glioblastoma.\",\n      \"evidence\": \"Co-IP, RNA-seq, ChIP, reporter assays, orthotopic and xenograft models\",\n      \"pmids\": [\"33269540\", \"32309805\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interfaces not mapped\", \"Tissue-specificity of partner selection unexplained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved PELP1's structural role as the central scaffold of the human Rix1 complex with WDR18/TEX10/SENP3, with a cryo-EM structure showing its LxxLL motifs are not configured for steroid receptor binding in this context — implying WDR18 association partitions PELP1 away from coactivation.\",\n      \"evidence\": \"Cryo-EM at 2.7 Å of the PELP1 Rix1 domain–WDR18 subcomplex, in vitro reconstitution\",\n      \"pmids\": [\"36351913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PELP1 partitions between Rix1 and coactivator pools in cells unresolved\", \"Functional output of the rixosome in cancer not directly tested here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified SETDB1 as a PELP1 partner required for Akt methylation and tamoxifen resistance, and validated PELP1 as a druggable target via SMIP34, which binds PELP1 and triggers its proteasomal degradation, suppressing both extranuclear and ribosome-biogenesis functions.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, co-IP, in vitro methylation; SMIP34 binding assays, RNA-seq, xenograft/PDX models\",\n      \"pmids\": [\"35395812\", \"35950923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SMIP34 binding site on PELP1 not crystallographically defined\", \"Clinical translation not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the structural mechanism for PELP1's rixosome scaffolding, showing its C-terminal IDR engages MDN1, histones, and SENP3, that its glutamate-rich region chaperones the histone octamer, and that a SLiM-SENP3 crystal structure explains allosteric activation of SUMO protease activity.\",\n      \"evidence\": \"X-ray crystallography of SLiM-SENP3, in vitro histone chaperoning, biochemical reconstitution\",\n      \"pmids\": [\"40712028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo SUMO substrates of the PELP1-activated rixosome not defined\", \"Integration with PELP1's coactivator functions unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PELP1 partitions between its nuclear receptor coactivator, chromatin-remodeling, extranuclear signaling, and rixosome scaffolding roles — and what governs the localization and PTM states that toggle between them — remains the central open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of how subcellular localization is regulated\", \"Competition between WDR18/Rix1 binding and SR coactivation not quantified in cells\", \"Causative role in any Mendelian disease not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 4, 9, 30, 35]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [15, 21]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3, 4, 15, 21]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 8, 31, 34]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [34]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 27, 29]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 8, 5, 24]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 4, 15, 21]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 15, 21, 20]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [31, 34, 18]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 17]}\n    ],\n    \"complexes\": [\n      \"Rix1 complex / rixosome (PELP1-WDR18-TEX10-SENP3)\",\n      \"ERα-cSrc-p85/PI3K non-genomic signaling complex\",\n      \"ER/PR/PELP1/IGF1R transcription complex\"\n    ],\n    \"partners\": [\n      \"ESR1\",\n      \"SRC\",\n      \"KDM1A\",\n      \"CARM1\",\n      \"WDR18\",\n      \"SENP3\",\n      \"RB1\",\n      \"NCOA3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}