{"gene":"PPP1R13L","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2003,"finding":"iASPP (encoded by PPP1R13L) is an evolutionarily conserved inhibitor of p53; inhibition of iASPP by RNA-mediated interference or antisense RNA in C. elegans or human cells induces p53-dependent apoptosis. iASPP cooperates with Ras, E1A, and E7 (but not mutant p53) to transform cells in vitro, establishing it as an oncoproteein that suppresses p53-mediated apoptosis.","method":"RNA interference in C. elegans and antisense RNA in human cells; oncogenic cooperation/transformation assays in vitro","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function in two organisms with defined p53-dependent apoptosis phenotype; replicated across species","pmids":["12524540"],"is_preprint":false},{"year":2006,"finding":"iASPP binds to the proline-rich region (PRR) of p53 in addition to the DNA-binding domain. iASPP preferentially binds and inhibits the p53Pro72 variant over p53Arg72, providing a mechanism by which p53Arg72 activates apoptosis more efficiently.","method":"Binding assays between ASPP family members and p53 PRR; functional apoptosis assays with p53 codon 72 polymorphic variants","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding demonstrated with functional consequence, replicated across ASPP family members","pmids":["16964264"],"is_preprint":false},{"year":2004,"finding":"iASPP exists as a longer isoform (828 aa) with an N-terminal extension that is predominantly cytoplasmic, causing the full-length iASPP to localize to both cytoplasm and nucleus, whereas the shorter iASPP(RAI) is predominantly nuclear. The N-terminus of iASPP is required for cytoplasmic localization. Both isoforms bind p53 and inhibit p53-induced apoptosis.","method":"Subcellular fractionation, immunofluorescence, reporter assays; p53 binding and apoptosis inhibition assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional binding/apoptosis validation, single lab, multiple orthogonal methods","pmids":["15489900"],"is_preprint":false},{"year":2007,"finding":"Pin1 (prolyl isomerase) mediates dissociation of p53 from the apoptosis inhibitor iASPP after phosphorylation of p53 at Ser46 by cytotoxic stimuli, thereby promoting p53-dependent cell death. Pin1 is required for efficient p53 loading onto target promoters and stimulates p300-mediated p53 acetylation.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, reporter assays, mutagenesis of Pin1-binding residues","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP, mutagenesis, and functional apoptosis assay in single rigorous study","pmids":["17906639"],"is_preprint":false},{"year":2011,"finding":"iASPP interacts with PP1 (protein phosphatase 1) via a noncanonical RNYF motif located within its SH3 domain, distinct from the canonical RVXF motif used by ASPP2. Phe-815 is critical for iASPP/PP1 interaction; iASPP(F815A) fails to inhibit p53 transcriptional and apoptotic function.","method":"Co-immunoprecipitation, GST pulldown, site-directed mutagenesis (F815A), functional p53 apoptosis assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding assay with active-site mutagenesis and functional validation, single lab","pmids":["21998301"],"is_preprint":false},{"year":2011,"finding":"iASPP is a binding partner and negative regulator of p65RelA (NF-κB subunit) as well as p53. In stratified epithelia, nuclear iASPP co-localizes with p63 in basal keratinocytes; iASPP binds p63 and inhibits transcriptional activity of both TAp63α and ΔNp63α, regulating epithelial stratification and preventing premature senescence in mouse embryonic fibroblasts.","method":"Transgenic mouse (Cre/loxP iASPP knockout), Co-IP, reporter assays, in vivo keratinocyte differentiation assays, immunofluorescence co-localization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout mouse model with defined cellular phenotypes, Co-IP binding validation, in vitro and in vivo corroboration","pmids":["21930934"],"is_preprint":false},{"year":2011,"finding":"iASPP promotes resistance to paclitaxel by reducing mitotic catastrophe in a p53-independent manner via activation of separase, with both securin and cyclin B1/CDK1 complex involved in regulating separase activity downstream of iASPP.","method":"iASPP overexpression and knockdown in ovarian cancer cells; functional mitotic catastrophe, apoptosis, and separase activity assays","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean gain/loss-of-function with defined mechanistic phenotype (separase activation), single lab","pmids":["21926165"],"is_preprint":false},{"year":2013,"finding":"Cyclin B1/CDK1 phosphorylates iASPP, leading to inhibition of iASPP dimerization, promotion of iASPP monomer nuclear entry, and exposure of its p53-binding sites, resulting in increased p53 inhibition. Phosphorylated nuclear iASPP is enriched in melanoma metastasis.","method":"Phosphorylation assays, dimerization assays, nuclear fractionation, small-molecule CDK1 inhibition, co-immunoprecipitation; crystal structure data cited for binding sites","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical and cell biological methods establishing CDK1-mediated phosphorylation mechanism with functional consequence, single lab","pmids":["23623661"],"is_preprint":false},{"year":2012,"finding":"iASPP inhibits p53-independent apoptosis by inhibiting the transcriptional activity of p63 and p73 on promoters of proapoptotic genes.","method":"Reporter assays for p63/p73 transcriptional activity; iASPP knockdown/overexpression; apoptosis assays in p53-deficient tumor cells","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean functional assays with defined transcriptional mechanism, single lab","pmids":["22538442"],"is_preprint":false},{"year":2015,"finding":"iASPP interacts with desmoplakin and desmin in cardiomyocytes to maintain the integrity of desmosomes and intermediate filament networks. iASPP deficiency induces right ventricular dilatation and causes ARVC-like sudden cardiac death in mice. ARVC-derived desmoplakin mutants (DSP-1-V30M and DSP-1-S299R) show weaker binding to iASPP.","method":"Co-immunoprecipitation, iASPP knockout mouse model (Ppp1r13lΔ8/Δ8), in vitro desmosome integrity assays, immunofluorescence at intercalated discs, human ARVC tissue analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with desmoplakin/desmin, genetic knockout mouse with defined cardiac phenotype, mutagenesis in human disease variants, replicated in vitro and in vivo","pmids":["25691752"],"is_preprint":false},{"year":2017,"finding":"iASPP competes with Nrf2 for Keap1 binding via a DLT motif, leading to decreased Nrf2 ubiquitination, increased Nrf2 accumulation, nuclear translocation, and antioxidative transactivation. This iASPP-Keap1-Nrf2 axis promotes cancer growth and drug resistance independently of p53.","method":"Co-immunoprecipitation, competitive binding assays, ubiquitination assays, Nrf2 nuclear translocation assays, DLT motif mutagenesis; in vitro and in vivo tumor growth assays","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — competitive binding, ubiquitination assay, mutagenesis of DLT motif, multiple orthogonal methods in single rigorous study","pmids":["29033244"],"is_preprint":false},{"year":2014,"finding":"iASPP acts as an autophagy inhibitor in keratinocytes by specifically reducing the interaction of Atg5-Atg12 with Atg16L1, an interaction essential for autophagosome formation or maturation. iASPP depletion activates autophagy and modulates mTORC1 signaling and mitochondrial dynamics.","method":"iASPP siRNA knockdown, LC3 lipidation assay, Co-IP of Atg5-Atg12/Atg16L1 complex, organotypic culture differentiation assay, mitochondrial imaging","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP demonstrating specific complex disruption with defined autophagy phenotype, single lab","pmids":["24777476"],"is_preprint":false},{"year":2015,"finding":"iASPP stabilizes p300 and CBP (histone acetyltransferases) by interfering with BRMS1-mediated ubiquitination of p300/CBP, thereby contributing to apoptotic susceptibility via TAp73-dependent transcription of pro-apoptotic genes.","method":"Co-immunoprecipitation, iASPP shRNA knockdown, ubiquitination assays, reporter assays for TAp73 target promoters, apoptosis assays upon cisplatin treatment","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and ubiquitination assays with functional apoptosis readout, single lab","pmids":["25675294"],"is_preprint":false},{"year":2015,"finding":"Caspase cleaves the N-terminal region of iASPP at SSLD294 upon apoptotic stimuli, generating an 80 kDa fragment that translocates from cytoplasm to nucleus via the RaDAR nuclear import pathway (independent of p53). This 80 kDa fragment binds and inhibits p53 or RelA/p65 more efficiently than full-length iASPP.","method":"Caspase cleavage assays, site identification by mutagenesis (SSLD294), subcellular fractionation, nuclear import pathway analysis, Co-IP with p53 and RelA/p65","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — caspase cleavage site mutagenesis with subcellular fractionation and binding assays, single lab","pmids":["26646590"],"is_preprint":false},{"year":2018,"finding":"iASPP acts as a PP1-targeting subunit (regulatory subunit) to facilitate interaction between PP1 and CEP55, promoting dephosphorylation of PLK1-mediated Ser436 phosphorylation in CEP55 during late mitosis, which is required for timely CEP55 recruitment to the midbody. iASPP depletion causes abnormal midbody structure and failed cytokinesis.","method":"Protein affinity purification, Co-IP, iASPP depletion with cytokinesis phenotype assays, phosphorylation assays for CEP55-Ser436","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — affinity purification plus Co-IP identifying CEP55 as substrate; dephosphorylation assay with defined cytokinesis phenotype on depletion, single lab","pmids":["29743530"],"is_preprint":false},{"year":2019,"finding":"Crystal structure of the p53-iASPP complex reveals that iASPP displaces the p53 L1 loop (which mediates sequence-specific DNA interactions) without perturbing other DNA-recognizing modules of the p53 DNA-binding domain. iASPP modulates p53 DNA-binding site selectivity through this mechanism. The iASPP binding surface overlaps with the HPV E6 footprint on p53, distinct from other p53-binding tumor suppressors/oncoproteins.","method":"X-ray crystallography (crystal structure of p53-iASPP complex); genome-wide p53 binding site sequence analysis; functional validation of selectivity","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation, mechanistically defines inhibition mechanism at atomic resolution","pmids":["31395738"],"is_preprint":false},{"year":2018,"finding":"iASPP physically interacts with CD44 standard isoform (CD44s) via the ankyrin-binding domain of CD44s. Hyaluronan stimulation promotes formation of iASPP-CD44s complexes in fibroblasts. CD44 alters subcellular localization of the iASPP-p53 complex; ablation of CD44 promotes translocation of iASPP from nucleus to cytoplasm, increasing cytoplasmic iASPP-p53 complex formation. iASPP is required for hyaluronan-induced CD44-dependent fibroblast migration.","method":"Co-immunoprecipitation, subcellular fractionation, siRNA knockdown, migration/adhesion assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reciprocal Co-IP with functional migration assay, single lab","pmids":["36831425"],"is_preprint":false},{"year":2017,"finding":"PPP1R13L (iASPP) directly inhibits the transcriptional activity of SP1 via protein-protein interaction. SP1 in turn transcriptionally activates PPP1R13L expression, forming a feedback loop that regulates nicotine-induced epithelial-mesenchymal transition in lung cancer cells.","method":"Co-immunoprecipitation demonstrating iASPP-SP1 protein interaction; reporter assays; EMT cell model with nicotine treatment","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and reporter assays establishing direct interaction and feedback, single lab","pmids":["36372331"],"is_preprint":false},{"year":2022,"finding":"iASPP suppresses Gp78-mediated ubiquitination and degradation of TMCO1 (a Ca2+-channel protein) by competitively binding with Gp78, thereby reducing ER Ca2+ stores and modulating Ca2+ homeostasis. This iASPP-TMCO1 axis promotes tumor growth and drug resistance.","method":"Co-immunoprecipitation, competitive binding assays, ubiquitination assays at K186 of TMCO1, Ca2+ measurement assays, in vitro and in vivo tumor growth assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — competitive binding Co-IP, ubiquitination site identification, Ca2+ functional assay, multiple orthogonal methods, single lab","pmids":["35121659"],"is_preprint":false},{"year":2022,"finding":"iASPP directly binds VHL at its β domain (which also binds HIF-1α), blocking VHL-mediated ubiquitination and degradation of HIF-1α under normoxia. This stabilizes HIF-1α and promotes angiogenesis and glycolysis in cancer cells.","method":"Co-immunoprecipitation, competitive binding assays between iASPP, VHL, and HIF-1α, iASPP genetic inhibition with HIF-1α protein level measurement, in vivo tumor growth assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding competition assay, functional HIF-1α stabilization and downstream targets, in vivo validation, single lab","pmids":["35169254"],"is_preprint":false},{"year":2022,"finding":"During prolonged ER stress, iASPP mRNA stabilization by HuR is impaired, reducing iASPP protein. iASPP competes with GRP78 for binding the ER-resident E3 ligase RNF185; when iASPP levels fall, GRP78 is degraded by RNF185, facilitating transition to terminal UPR and cell death.","method":"Co-immunoprecipitation (iASPP vs GRP78 competition for RNF185), iASPP knockdown/overexpression with GRP78 stability assays, HuR mRNA stabilization assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP demonstrating competitive binding with functional consequence, single lab","pmids":["36380064"],"is_preprint":false},{"year":2017,"finding":"PPP1R13L loss-of-function (homozygous stop codon) causes a cardio-cutaneous syndrome in humans. In patient fibroblasts and iASPP-deficient cardiomyocytes, the NF-κB-dependent inflammatory response to LPS is hypersensitive; iASPP normally dampens NF-κB binding activity at promoters of pro-inflammatory cytokine genes.","method":"Human genetics (identifying PPP1R13L premature stop codon), NF-κB EMSA and ChIP on patient fibroblasts, siRNA knockdown of Ppp1r13l in murine cardiomyocytes, RNA sequencing of Ppp1r13l-deficient mouse hearts","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetic loss-of-function combined with NF-κB EMSA/ChIP mechanistic studies and mouse model, replicated across cell types and species","pmids":["28069640"],"is_preprint":false},{"year":2018,"finding":"In cardiomyocyte-specific iASPP-deficient mice, loss of iASPP is sufficient to cause cardiac disorder; in keratinocyte-specific iASPP-deficient mice, loss of iASPP causes cutaneous disorder, delayed eyelid development, and impaired wound healing. Junctional iASPP in keratinocytes is critical for desmosome stabilization; its deficiency results in increased and disorganized cell migration and impaired cell adhesion.","method":"Cardiomyocyte-specific and keratinocyte-specific Cre/loxP iASPP knockout mice, desmosome integrity assays, cell migration and adhesion assays, wound healing models","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic knockouts with defined mechanistic phenotypes in desmosome integrity and wound healing","pmids":["29352264"],"is_preprint":false},{"year":2009,"finding":"Overexpression of PPP1R13L promotes p53 degradation via the proteasome, depletes active p65/RelA, and accelerates tumor formation driven by RAS/E1A, modulating both p53-dependent and p53-independent apoptosis pathways.","method":"Overexpression in primary MEFs (with/without p53); proteasome inhibitor (MG132) experiments; in vivo tumor formation assays","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic overexpression with proteasome inhibitor mechanistic dissection, single lab","pmids":["19263435"],"is_preprint":false},{"year":2015,"finding":"iASPP is identified as an ERK-primed GSK-3 substrate; in the presence of GSK-3, iASPP is targeted for degradation, linking KSHV LANA-mediated kinase dysregulation to iASPP stability.","method":"Protein microarray phosphorylation screen, cotransfection with GSK-3, proteasome-dependent degradation assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — microarray screen followed by cotransfection confirmation and degradation assay, single lab","pmids":["26109723"],"is_preprint":false},{"year":2017,"finding":"CDK1 (cyclin-dependent kinase 1) physically interacts with iASPP protein; this interaction affects colorectal cancer cell proliferation and apoptosis through the p53 apoptosis pathway.","method":"GST pulldown assay, Co-immunoprecipitation, cell proliferation and apoptosis assays with CDK1 and iASPP manipulations","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — GST pulldown and Co-IP confirming direct interaction, single lab","pmids":["29069733"],"is_preprint":false},{"year":2021,"finding":"iASPP associates with the microtubule plus-end binding protein EB1 via an SxIP motif, and with Myosin-Ic (Myo1c). iASPP loss or mutation of its SxIP motif leads to defective microtubule capture at the cortex of mitotic cells, abnormal mitotic spindle positioning, and failure of cells to round up during mitosis due to defective cortical stiffness.","method":"Co-immunoprecipitation, SxIP motif mutagenesis, iASPP and Myo1c siRNA knockdown, atomic force microscopy for cortical stiffness, live imaging of mitotic spindle","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, site-specific mutagenesis, multiple functional readouts (stiffness, spindle positioning), single lab with multiple orthogonal methods","pmids":["34705028"],"is_preprint":false},{"year":2022,"finding":"JNK-mediated phosphorylation of iASPP inhibits iASPP binding with AP1 components (such as JUND) via PXXP/SH3 domain-mediated interaction. iASPP regulates expression of a subset of p63 and AP1 target genes involved in skin differentiation and inflammation, acting as a tumor suppressor in RAS-driven, inflammation-promoted skin tumorigenesis.","method":"JNK phosphorylation assays, Co-IP of iASPP with JUND, iASPP loss-of-function in RAS/inflammation-driven mouse skin tumor model, gene expression profiling","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — kinase-substrate phosphorylation with Co-IP and in vivo mouse model, single lab","pmids":["36261000"],"is_preprint":false},{"year":2023,"finding":"iASPP suppresses KRAS-driven and inflammation-driven pancreatic cancer tumorigenesis and acinar-to-ductal metaplasia in a p53-independent manner; transcriptomic analysis shows iASPP deletion and p53 mutation overlap extensively in NF-κB and AP1-regulated inflammatory gene sets.","method":"Genetic mouse models (KRASG12D with iASPPΔ8/Δ8), in vitro ADM assays, syngeneic/nude mouse tumor models, RNA sequencing","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic double-mutant mouse models establishing epistatic relationship, multiple tumor models, transcriptomic mechanistic profiling","pmids":["37270580"],"is_preprint":false},{"year":2018,"finding":"iASPP interacts with NAF-1 (a NEET 2Fe-2S protein); peptide mapping and computational analysis localized the interaction to residues 764-778 of iASPP binding a surface groove of NAF-1. This iASPP-NAF-1 interaction is stimulated during apoptosis in cancer cells and is required for apoptosis activation.","method":"Peptide array screening, computational modeling, cell-based interaction assay, apoptosis inhibition assay with iASPP 764-780 peptide in cancer cells","journal":"Chemical science","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — peptide array and cell-based assay without full structural or Co-IP validation, single lab","pmids":["30774867"],"is_preprint":false},{"year":2021,"finding":"Measles virus C protein specifically interacts with the p65-iASPP protein complex, as determined by affinity purification/mass spectrometry and protein complementation assay, potentially hijacking the cell death and innate immunity regulatory functions of this complex.","method":"Affinity purification coupled to mass spectrometry, protein complementation assay (PCA), bioluminescence resonance energy transfer (BRET)","journal":"Molecular & cellular proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — AP-MS plus PCA/BRET orthogonal validation, single lab; functional consequence in viral context not fully established","pmids":["33515806"],"is_preprint":false},{"year":2020,"finding":"iASPP inhibits chemotherapy-induced senescence (TIS) by translocating to the nucleus in senescent cells (driven by NF-κBp65 transcriptional induction), where it binds p53 and NF-κBp65, inhibiting their transcriptional activation of p21 and SASP factors IL-6/IL-8, thereby preventing senescence and conferring drug resistance independently of apoptosis.","method":"iASPP knockdown in HCT116 and MCF-7 cells, xenograft model, Co-IP of iASPP with p53 and p65, reporter assays, senescence markers (SA-β-Gal, p21)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and reporter assays with functional senescence phenotype in vitro and in vivo, single lab","pmids":["32005663"],"is_preprint":false},{"year":2017,"finding":"FHL2 is a binding partner of iASPP (identified by yeast two-hybrid screen and confirmed by Co-IP); FHL2 and iASPP co-localize in both nucleus and cytoplasm of leukemia cells. When FHL2 is knocked down, iASPP protein expression also decreases, and vice versa, suggesting mutual stabilization.","method":"Yeast two-hybrid screen, Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, Western blot","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid with Co-IP confirmation, single lab","pmids":["28402264"],"is_preprint":false},{"year":2010,"finding":"NF-κB increases expression of iASPP through p65/p50 binding to a putative NF-κB-binding site in the iASPP promoter; hepatitis B virus X protein upregulates iASPP expression via NF-κB activation.","method":"Luciferase reporter assay, chromatin immunoprecipitation, electrophoretic mobility shift assay (EMSA)","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP plus EMSA plus reporter assay establishing direct transcriptional regulation, multiple methods, single lab","pmids":["20600029"],"is_preprint":false},{"year":2010,"finding":"p53 and PPP1R13L form a negative feedback loop: p53 accumulation after DNA damage drives PPP1R13L expression (dependent on p53 target genes BAX and GADD45α), while PPP1R13L in turn inhibits p53 function. Proteasome inhibition leads to accumulation of both p53 and PPP1R13L.","method":"siRNA knockdown of p53, PPP1R13L, BAX, and GADD45α; Western blot, qPCR, proteasome inhibitor (MG132) treatment in human and mouse cells with varying p53 status","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — systematic siRNA epistasis across multiple cell lines with multiple pathway nodes, single lab","pmids":["20840860"],"is_preprint":false},{"year":2014,"finding":"iASPP phosphorylation at serine residues (which increases iASPP affinity toward p53) is significantly reduced following optic nerve axotomy in retinal ganglion cells (RGCs). iASPP knockdown exacerbates RGC death after axotomy; AAV-mediated iASPP overexpression promotes RGC survival and downregulates p53 activity and pro-apoptotic targets PUMA and Fas/CD95.","method":"siRNA knockdown, AAV-mediated overexpression, in vivo optic nerve axotomy model, phospho-specific Western blot, p53 target gene expression analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo gain/loss-of-function with mechanistic p53 pathway readouts, single lab","pmids":["24714389"],"is_preprint":false}],"current_model":"iASPP (PPP1R13L) is a multifunctional scaffolding protein and predicted PP1 regulatory subunit that inhibits p53 transcriptional activity by contacting the p53 DNA-binding domain and displacing the L1 loop (established by crystal structure), while also suppressing p63, p73, and NF-κB/RelA; it is phosphorylated by cyclin B1/CDK1 to drive nuclear entry and enhanced p53 inhibition, dephosphorylated via an iASPP-PP1 complex it assembles (requiring its noncanonical RNYF/SH3 motif), cleaved by caspases at SSLD294 to generate a more potent nuclear inhibitory fragment, and it acts outside apoptosis by binding Keap1 to stabilize Nrf2 and reduce ROS, binding VHL to stabilize HIF-1α, binding GRP78-competing E3 ligase RNF185 to regulate ER stress responses, binding TMCO1-targeting E3 ligase Gp78 to regulate Ca2+ homeostasis, interacting with desmoplakin and desmin at intercalated discs to maintain desmosome integrity, associating with EB1 via an SxIP motif and Myosin-Ic to regulate mitotic cortical stiffness and spindle positioning, and facilitating CEP55 dephosphorylation for cytokinetic abscission—collectively placing iASPP at the intersection of apoptosis, oxidative stress, ER homeostasis, Ca2+ signaling, cell division, and desmosomal integrity."},"narrative":{"mechanistic_narrative":"PPP1R13L (iASPP) is an evolutionarily conserved oncoprotein and multifunctional scaffold whose canonical role is inhibition of p53-dependent apoptosis [PMID:12524540]. It binds the p53 DNA-binding domain and proline-rich region, and the crystal structure of the p53-iASPP complex shows it displaces the p53 L1 loop to reshape DNA-binding site selectivity along a surface overlapping the HPV E6 footprint [PMID:16964264, PMID:31395738]. iASPP function is governed by tightly regulated subcellular partitioning and post-translational control: cyclin B1/CDK1 phosphorylation disrupts iASPP dimerization, drives nuclear entry of the monomer, and exposes its p53-binding sites to enhance p53 inhibition [PMID:23623661], while caspase cleavage at SSLD294 generates an 80 kDa nuclear fragment that inhibits p53 and RelA/p65 more potently than the full-length protein [PMID:26646590]. iASPP also acts as a noncanonical PP1-targeting subunit, engaging PP1 through an RNYF motif in its SH3 domain that is required for p53 inhibition [PMID:21998301]. Its repressive activity extends beyond p53 to the p53-family transcription factors p63 and p73 and to NF-κB/RelA, integrating control of epithelial stratification, inflammation, and apoptosis [PMID:21930934, PMID:22538442, PMID:28069640]. Independently of apoptosis, iASPP stabilizes stress-response and homeostatic effectors by competing with E3-ligase or adaptor partners: it competes with Nrf2 for Keap1 to suppress Nrf2 ubiquitination and reduce ROS [PMID:29033244], binds VHL to block HIF-1α degradation [PMID:35169254], competes with Gp78 to protect the Ca2+ channel TMCO1 [PMID:35121659], and competes with GRP78 for the ER-resident ligase RNF185 to modulate the unfolded-protein response [PMID:36380064]. During cell division, iASPP couples to the cytoskeleton and mitotic machinery: it associates with EB1 via an SxIP motif and with Myosin-Ic to control cortical stiffness and spindle positioning [PMID:34705028], and targets PP1 to dephosphorylate CEP55 for cytokinetic abscission [PMID:29743530]. At desmosomes, iASPP binds desmoplakin and desmin to maintain intercalated-disc integrity [PMID:25691752]. Loss-of-function PPP1R13L mutation causes a human cardio-cutaneous syndrome with hypersensitive NF-κB-driven inflammation, and iASPP-deficient mice develop ARVC-like cardiac disease and cutaneous defects [PMID:25691752, PMID:28069640, PMID:29352264].","teleology":[{"year":2003,"claim":"Established iASPP as a conserved inhibitor of p53 whose loss triggers p53-dependent apoptosis, defining it as an oncoprotein rather than a passive binding partner.","evidence":"RNAi in C. elegans and antisense RNA in human cells plus oncogenic transformation assays","pmids":["12524540"],"confidence":"High","gaps":["Did not define the molecular contact surface on p53","Did not address p53-independent roles"]},{"year":2004,"claim":"Resolved that iASPP has cytoplasmic and nuclear isoforms, framing localization control as central to its activity.","evidence":"Subcellular fractionation, immunofluorescence and functional p53/apoptosis assays on long and short isoforms","pmids":["15489900"],"confidence":"High","gaps":["Did not identify the signals or modifications driving nuclear translocation","Isoform-specific functional differences beyond localization unresolved"]},{"year":2006,"claim":"Defined the p53 proline-rich region as an additional iASPP contact and linked the codon-72 polymorphism to differential apoptotic output.","evidence":"Binding assays with p53 PRR and apoptosis assays in polymorphic variants","pmids":["16964264"],"confidence":"High","gaps":["Atomic basis of selectivity not yet resolved"]},{"year":2007,"claim":"Showed that stress-induced p53 Ser46 phosphorylation and Pin1 actively dissociate the iASPP-p53 complex, establishing a regulated switch from inhibition to apoptosis.","evidence":"Co-IP, ChIP, reporter assays and Pin1-binding mutagenesis","pmids":["17906639"],"confidence":"High","gaps":["Direct iASPP residues targeted by this switch not mapped"]},{"year":2009,"claim":"Linked iASPP overexpression to proteasomal p53 degradation and RAS/E1A-driven tumorigenesis, extending its action to p53 turnover.","evidence":"Overexpression in MEFs with MG132 and in vivo tumor formation","pmids":["19263435"],"confidence":"Medium","gaps":["Mechanism by which iASPP promotes p53 degradation not defined","No direct ligase identified"]},{"year":2010,"claim":"Embedded iASPP in transcriptional feedback loops with both p53 and NF-κB, showing it is itself an inducible node responsive to DNA damage and viral signals.","evidence":"siRNA epistasis (p53/BAX/GADD45α), ChIP, EMSA and reporter assays; HBx induction via NF-κB","pmids":["20840860","20600029"],"confidence":"Medium","gaps":["Quantitative dynamics of the feedback loops not modeled","Promoter occupancy in physiological settings limited"]},{"year":2011,"claim":"Identified iASPP as a noncanonical PP1-targeting subunit and broadened its transcriptional targets to p63 and NF-κB/RelA, revealing scaffold and phosphatase-recruitment functions beyond p53.","evidence":"RNYF/F815A mutagenesis with GST pulldown; knockout mouse with keratinocyte phenotypes and Co-IP for p63/RelA","pmids":["21998301","21930934"],"confidence":"High","gaps":["PP1 substrates recruited by iASPP not yet enumerated","Structural basis of the noncanonical RNYF/PP1 interface unresolved"]},{"year":2011,"claim":"Connected iASPP to mitotic survival via separase activation, an early indication of p53-independent roles in cell division.","evidence":"Gain/loss-of-function in ovarian cancer cells with separase activity and mitotic catastrophe assays","pmids":["21926165"],"confidence":"Medium","gaps":["Direct molecular link between iASPP and separase not established","Single cell-type context"]},{"year":2013,"claim":"Defined cyclin B1/CDK1 phosphorylation as the switch that disassembles iASPP dimers, drives nuclear entry, and exposes p53-binding sites, mechanistically coupling cell-cycle state to p53 inhibition.","evidence":"Phosphorylation, dimerization and nuclear fractionation assays with CDK1 inhibition; melanoma metastasis correlation","pmids":["23623661"],"confidence":"High","gaps":["Phosphosite residues and their stoichiometry only partly defined","Phosphatase reversing this in vivo not identified here"]},{"year":2014,"claim":"Revealed apoptosis-independent roles in autophagy and neuronal survival, showing iASPP modulates Atg complex assembly and that its phospho-state tracks injury-induced p53 activity.","evidence":"siRNA with LC3 lipidation and Atg5-Atg12/Atg16L1 Co-IP; in vivo optic nerve axotomy with phospho-specific blotting","pmids":["24777476","24714389"],"confidence":"Medium","gaps":["Direct iASPP-Atg interaction surface not mapped","Kinase/phosphatase controlling RGC iASPP phospho-state unknown"]},{"year":2015,"claim":"Established structural roles at desmosomes and additional regulators of apoptotic competence, broadening iASPP from a transcriptional inhibitor to a cytoarchitectural and acetyltransferase-stabilizing scaffold.","evidence":"Reciprocal Co-IP with desmoplakin/desmin and knockout mouse with ARVC-like phenotype; p300/CBP ubiquitination and caspase cleavage-site (SSLD294) mutagenesis with fractionation","pmids":["25691752","25675294","26646590"],"confidence":"High","gaps":["How desmosomal and nuclear pools are partitioned unclear","Functional impact of the 80 kDa fragment in vivo not established"]},{"year":2017,"claim":"Identified the iASPP-Keap1-Nrf2 axis and a human loss-of-function disease, linking iASPP to oxidative-stress control, NF-κB-driven inflammation, and a defined cardio-cutaneous syndrome.","evidence":"DLT-motif competitive binding and ubiquitination assays for Keap1/Nrf2; human PPP1R13L stop-codon genetics with NF-κB EMSA/ChIP and mouse models","pmids":["29033244","28069640"],"confidence":"High","gaps":["Tissue-specific balance between oncogenic and tumor-suppressive functions unresolved","How a single locus produces both cardiac and cutaneous phenotypes only partly explained"]},{"year":2018,"claim":"Defined iASPP as a PP1-CEP55 targeting factor required for cytokinetic abscission and identified additional protein partners, deepening its mitotic and homeostatic roles.","evidence":"Affinity purification/Co-IP with CEP55-Ser436 dephosphorylation and cytokinesis phenotypes; cell-type-specific knockout mice; NAF-1 peptide mapping","pmids":["29743530","29352264","30774867"],"confidence":"High","gaps":["NAF-1 interaction lacks Co-IP/structural confirmation","Coordination of mitotic versus interphase iASPP pools unclear"]},{"year":2019,"claim":"Resolved the atomic mechanism of p53 inhibition: iASPP displaces the p53 L1 loop to alter DNA-binding site selectivity, distinguishing it from other p53-binding regulators.","evidence":"X-ray crystallography of the p53-iASPP complex with genome-wide binding-site analysis","pmids":["31395738"],"confidence":"High","gaps":["Structures of iASPP with p63/p73 or RelA not determined","How phosphorylation alters the structural interface not visualized"]},{"year":2022,"claim":"Expanded the competitive-binding paradigm to VHL/HIF-1α, Gp78/TMCO1, and RNF185/GRP78, establishing iASPP as a general antagonist of E3-ligase substrate recognition controlling hypoxia, Ca2+, and ER-stress responses.","evidence":"Competitive Co-IP and ubiquitination assays with functional HIF-1α, Ca2+, and UPR readouts plus in vivo tumor models; EB1/Myo1c SxIP work on cortical mechanics","pmids":["35169254","35121659","36380064","34705028"],"confidence":"High","gaps":["Whether one iASPP molecule integrates these axes or distinct pools act separately is unknown","Determinants of partner selectivity among competing E3 systems unresolved"]},{"year":2023,"claim":"Demonstrated a context-dependent tumor-suppressive role in KRAS- and inflammation-driven cancers acting through NF-κB/AP1 gene sets, sharpening the dual oncogene/tumor-suppressor model.","evidence":"Genetic KRASG12D;iASPP-deletion mouse models with ADM assays and RNA-seq; JNK-AP1/JUND phosphoregulation in skin tumorigenesis","pmids":["37270580","36261000"],"confidence":"High","gaps":["Molecular determinant switching iASPP between oncogenic and suppressive output not identified","Relationship to its p53-inhibitory function in these tissues unclear"]},{"year":null,"claim":"It remains unknown how the multiple post-translational switches and competing partner pools are coordinated to assign iASPP to a specific function in a given cell state.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model relating phosphorylation, cleavage, and localization to partner choice","Full PP1 substrate repertoire targeted by iASPP undefined","Structural basis of non-p53 inhibitory complexes lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,5,8,15,17,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,10,14,18,19,20]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,9,14,26]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[26]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,7,13,15,31]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9,22,26]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[18,20]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,8,13,29]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,7,14,26]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[10,18,20]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,19,21]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,5,15]}],"complexes":["iASPP-PP1 complex","desmosome/intercalated disc"],"partners":["TP53","RELA","KEAP1","VHL","PPP1CA","CEP55","DSP","MAPRE1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WUF5","full_name":"RelA-associated inhibitor","aliases":["Inhibitor of ASPP protein","Protein iASPP","NFkB-interacting protein 1","PPP1R13B-like protein"],"length_aa":828,"mass_kda":89.1,"function":"Regulator that plays a central role in regulation of apoptosis and transcription via its interaction with NF-kappa-B and p53/TP53 proteins. Blocks transcription of HIV-1 virus by inhibiting the action of both NF-kappa-B and SP1. Also inhibits p53/TP53 function, possibly by preventing the association between p53/TP53 and ASPP1 or ASPP2, and therefore suppressing the subsequent activation of apoptosis (PubMed:12524540). 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sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31938994","citation_count":11,"is_preprint":false},{"pmid":"36831425","id":"PMC_36831425","title":"Hyaluronan-Induced CD44-iASPP Interaction Affects Fibroblast Migration and Survival.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36831425","citation_count":10,"is_preprint":false},{"pmid":"30128886","id":"PMC_30128886","title":"GLTSCR1, ATM, PPP1R13L and CD3EAP Genetic Variants and Lung Cancer Risk in a Chinese Population.","date":"2018","source":"Current medical science","url":"https://pubmed.ncbi.nlm.nih.gov/30128886","citation_count":10,"is_preprint":false},{"pmid":"29620255","id":"PMC_29620255","title":"Different splicing isoforms of ERCC1 affect the expression of its overlapping genes CD3EAP and PPP1R13L, and indicate a potential application in non-small cell lung cancer treatment.","date":"2018","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29620255","citation_count":10,"is_preprint":false},{"pmid":"26109723","id":"PMC_26109723","title":"A Screen for Extracellular Signal-Regulated Kinase-Primed Glycogen Synthase Kinase 3 Substrates Identifies the p53 Inhibitor iASPP.","date":"2015","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/26109723","citation_count":10,"is_preprint":false},{"pmid":"36746936","id":"PMC_36746936","title":"Regulation of immunological tolerance by the p53-inhibitor iASPP.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36746936","citation_count":9,"is_preprint":false},{"pmid":"34610339","id":"PMC_34610339","title":"Malignant transformation of human bronchial epithelial cells induced by benzo [a] pyrene suggests a negative feedback of TP53 to PPP1R13L via binding a possible enhancer element.","date":"2021","source":"Chemico-biological 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biological functions of leukemia cells.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28402264","citation_count":7,"is_preprint":false},{"pmid":"30105797","id":"PMC_30105797","title":"miR-129 targets CDK1 and iASPP to modulate Burkitt lymphoma cell proliferation in a TAp63-dependent manner.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30105797","citation_count":6,"is_preprint":false},{"pmid":"35933355","id":"PMC_35933355","title":"Novel homozygous stop-gain pathogenic variant of PPP1R13L gene leads to arrhythmogenic cardiomyopathy.","date":"2022","source":"BMC cardiovascular 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apoptosis.\",\n      \"method\": \"RNA interference in C. elegans and antisense RNA in human cells; oncogenic cooperation/transformation assays in vitro\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function in two organisms with defined p53-dependent apoptosis phenotype; replicated across species\",\n      \"pmids\": [\"12524540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"iASPP binds to the proline-rich region (PRR) of p53 in addition to the DNA-binding domain. iASPP preferentially binds and inhibits the p53Pro72 variant over p53Arg72, providing a mechanism by which p53Arg72 activates apoptosis more efficiently.\",\n      \"method\": \"Binding assays between ASPP family members and p53 PRR; functional apoptosis assays with p53 codon 72 polymorphic variants\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding demonstrated with functional consequence, replicated across ASPP family members\",\n      \"pmids\": [\"16964264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"iASPP exists as a longer isoform (828 aa) with an N-terminal extension that is predominantly cytoplasmic, causing the full-length iASPP to localize to both cytoplasm and nucleus, whereas the shorter iASPP(RAI) is predominantly nuclear. The N-terminus of iASPP is required for cytoplasmic localization. Both isoforms bind p53 and inhibit p53-induced apoptosis.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence, reporter assays; p53 binding and apoptosis inhibition assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional binding/apoptosis validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"15489900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Pin1 (prolyl isomerase) mediates dissociation of p53 from the apoptosis inhibitor iASPP after phosphorylation of p53 at Ser46 by cytotoxic stimuli, thereby promoting p53-dependent cell death. Pin1 is required for efficient p53 loading onto target promoters and stimulates p300-mediated p53 acetylation.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, reporter assays, mutagenesis of Pin1-binding residues\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP, mutagenesis, and functional apoptosis assay in single rigorous study\",\n      \"pmids\": [\"17906639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"iASPP interacts with PP1 (protein phosphatase 1) via a noncanonical RNYF motif located within its SH3 domain, distinct from the canonical RVXF motif used by ASPP2. Phe-815 is critical for iASPP/PP1 interaction; iASPP(F815A) fails to inhibit p53 transcriptional and apoptotic function.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, site-directed mutagenesis (F815A), functional p53 apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding assay with active-site mutagenesis and functional validation, single lab\",\n      \"pmids\": [\"21998301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"iASPP is a binding partner and negative regulator of p65RelA (NF-κB subunit) as well as p53. In stratified epithelia, nuclear iASPP co-localizes with p63 in basal keratinocytes; iASPP binds p63 and inhibits transcriptional activity of both TAp63α and ΔNp63α, regulating epithelial stratification and preventing premature senescence in mouse embryonic fibroblasts.\",\n      \"method\": \"Transgenic mouse (Cre/loxP iASPP knockout), Co-IP, reporter assays, in vivo keratinocyte differentiation assays, immunofluorescence co-localization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout mouse model with defined cellular phenotypes, Co-IP binding validation, in vitro and in vivo corroboration\",\n      \"pmids\": [\"21930934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"iASPP promotes resistance to paclitaxel by reducing mitotic catastrophe in a p53-independent manner via activation of separase, with both securin and cyclin B1/CDK1 complex involved in regulating separase activity downstream of iASPP.\",\n      \"method\": \"iASPP overexpression and knockdown in ovarian cancer cells; functional mitotic catastrophe, apoptosis, and separase activity assays\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean gain/loss-of-function with defined mechanistic phenotype (separase activation), single lab\",\n      \"pmids\": [\"21926165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cyclin B1/CDK1 phosphorylates iASPP, leading to inhibition of iASPP dimerization, promotion of iASPP monomer nuclear entry, and exposure of its p53-binding sites, resulting in increased p53 inhibition. Phosphorylated nuclear iASPP is enriched in melanoma metastasis.\",\n      \"method\": \"Phosphorylation assays, dimerization assays, nuclear fractionation, small-molecule CDK1 inhibition, co-immunoprecipitation; crystal structure data cited for binding sites\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical and cell biological methods establishing CDK1-mediated phosphorylation mechanism with functional consequence, single lab\",\n      \"pmids\": [\"23623661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"iASPP inhibits p53-independent apoptosis by inhibiting the transcriptional activity of p63 and p73 on promoters of proapoptotic genes.\",\n      \"method\": \"Reporter assays for p63/p73 transcriptional activity; iASPP knockdown/overexpression; apoptosis assays in p53-deficient tumor cells\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean functional assays with defined transcriptional mechanism, single lab\",\n      \"pmids\": [\"22538442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"iASPP interacts with desmoplakin and desmin in cardiomyocytes to maintain the integrity of desmosomes and intermediate filament networks. iASPP deficiency induces right ventricular dilatation and causes ARVC-like sudden cardiac death in mice. ARVC-derived desmoplakin mutants (DSP-1-V30M and DSP-1-S299R) show weaker binding to iASPP.\",\n      \"method\": \"Co-immunoprecipitation, iASPP knockout mouse model (Ppp1r13lΔ8/Δ8), in vitro desmosome integrity assays, immunofluorescence at intercalated discs, human ARVC tissue analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with desmoplakin/desmin, genetic knockout mouse with defined cardiac phenotype, mutagenesis in human disease variants, replicated in vitro and in vivo\",\n      \"pmids\": [\"25691752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"iASPP competes with Nrf2 for Keap1 binding via a DLT motif, leading to decreased Nrf2 ubiquitination, increased Nrf2 accumulation, nuclear translocation, and antioxidative transactivation. This iASPP-Keap1-Nrf2 axis promotes cancer growth and drug resistance independently of p53.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assays, ubiquitination assays, Nrf2 nuclear translocation assays, DLT motif mutagenesis; in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — competitive binding, ubiquitination assay, mutagenesis of DLT motif, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"29033244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"iASPP acts as an autophagy inhibitor in keratinocytes by specifically reducing the interaction of Atg5-Atg12 with Atg16L1, an interaction essential for autophagosome formation or maturation. iASPP depletion activates autophagy and modulates mTORC1 signaling and mitochondrial dynamics.\",\n      \"method\": \"iASPP siRNA knockdown, LC3 lipidation assay, Co-IP of Atg5-Atg12/Atg16L1 complex, organotypic culture differentiation assay, mitochondrial imaging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP demonstrating specific complex disruption with defined autophagy phenotype, single lab\",\n      \"pmids\": [\"24777476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"iASPP stabilizes p300 and CBP (histone acetyltransferases) by interfering with BRMS1-mediated ubiquitination of p300/CBP, thereby contributing to apoptotic susceptibility via TAp73-dependent transcription of pro-apoptotic genes.\",\n      \"method\": \"Co-immunoprecipitation, iASPP shRNA knockdown, ubiquitination assays, reporter assays for TAp73 target promoters, apoptosis assays upon cisplatin treatment\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and ubiquitination assays with functional apoptosis readout, single lab\",\n      \"pmids\": [\"25675294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Caspase cleaves the N-terminal region of iASPP at SSLD294 upon apoptotic stimuli, generating an 80 kDa fragment that translocates from cytoplasm to nucleus via the RaDAR nuclear import pathway (independent of p53). This 80 kDa fragment binds and inhibits p53 or RelA/p65 more efficiently than full-length iASPP.\",\n      \"method\": \"Caspase cleavage assays, site identification by mutagenesis (SSLD294), subcellular fractionation, nuclear import pathway analysis, Co-IP with p53 and RelA/p65\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — caspase cleavage site mutagenesis with subcellular fractionation and binding assays, single lab\",\n      \"pmids\": [\"26646590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"iASPP acts as a PP1-targeting subunit (regulatory subunit) to facilitate interaction between PP1 and CEP55, promoting dephosphorylation of PLK1-mediated Ser436 phosphorylation in CEP55 during late mitosis, which is required for timely CEP55 recruitment to the midbody. iASPP depletion causes abnormal midbody structure and failed cytokinesis.\",\n      \"method\": \"Protein affinity purification, Co-IP, iASPP depletion with cytokinesis phenotype assays, phosphorylation assays for CEP55-Ser436\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity purification plus Co-IP identifying CEP55 as substrate; dephosphorylation assay with defined cytokinesis phenotype on depletion, single lab\",\n      \"pmids\": [\"29743530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structure of the p53-iASPP complex reveals that iASPP displaces the p53 L1 loop (which mediates sequence-specific DNA interactions) without perturbing other DNA-recognizing modules of the p53 DNA-binding domain. iASPP modulates p53 DNA-binding site selectivity through this mechanism. The iASPP binding surface overlaps with the HPV E6 footprint on p53, distinct from other p53-binding tumor suppressors/oncoproteins.\",\n      \"method\": \"X-ray crystallography (crystal structure of p53-iASPP complex); genome-wide p53 binding site sequence analysis; functional validation of selectivity\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation, mechanistically defines inhibition mechanism at atomic resolution\",\n      \"pmids\": [\"31395738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"iASPP physically interacts with CD44 standard isoform (CD44s) via the ankyrin-binding domain of CD44s. Hyaluronan stimulation promotes formation of iASPP-CD44s complexes in fibroblasts. CD44 alters subcellular localization of the iASPP-p53 complex; ablation of CD44 promotes translocation of iASPP from nucleus to cytoplasm, increasing cytoplasmic iASPP-p53 complex formation. iASPP is required for hyaluronan-induced CD44-dependent fibroblast migration.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, siRNA knockdown, migration/adhesion assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reciprocal Co-IP with functional migration assay, single lab\",\n      \"pmids\": [\"36831425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PPP1R13L (iASPP) directly inhibits the transcriptional activity of SP1 via protein-protein interaction. SP1 in turn transcriptionally activates PPP1R13L expression, forming a feedback loop that regulates nicotine-induced epithelial-mesenchymal transition in lung cancer cells.\",\n      \"method\": \"Co-immunoprecipitation demonstrating iASPP-SP1 protein interaction; reporter assays; EMT cell model with nicotine treatment\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and reporter assays establishing direct interaction and feedback, single lab\",\n      \"pmids\": [\"36372331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"iASPP suppresses Gp78-mediated ubiquitination and degradation of TMCO1 (a Ca2+-channel protein) by competitively binding with Gp78, thereby reducing ER Ca2+ stores and modulating Ca2+ homeostasis. This iASPP-TMCO1 axis promotes tumor growth and drug resistance.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assays, ubiquitination assays at K186 of TMCO1, Ca2+ measurement assays, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — competitive binding Co-IP, ubiquitination site identification, Ca2+ functional assay, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"35121659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"iASPP directly binds VHL at its β domain (which also binds HIF-1α), blocking VHL-mediated ubiquitination and degradation of HIF-1α under normoxia. This stabilizes HIF-1α and promotes angiogenesis and glycolysis in cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assays between iASPP, VHL, and HIF-1α, iASPP genetic inhibition with HIF-1α protein level measurement, in vivo tumor growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding competition assay, functional HIF-1α stabilization and downstream targets, in vivo validation, single lab\",\n      \"pmids\": [\"35169254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"During prolonged ER stress, iASPP mRNA stabilization by HuR is impaired, reducing iASPP protein. iASPP competes with GRP78 for binding the ER-resident E3 ligase RNF185; when iASPP levels fall, GRP78 is degraded by RNF185, facilitating transition to terminal UPR and cell death.\",\n      \"method\": \"Co-immunoprecipitation (iASPP vs GRP78 competition for RNF185), iASPP knockdown/overexpression with GRP78 stability assays, HuR mRNA stabilization assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP demonstrating competitive binding with functional consequence, single lab\",\n      \"pmids\": [\"36380064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PPP1R13L loss-of-function (homozygous stop codon) causes a cardio-cutaneous syndrome in humans. In patient fibroblasts and iASPP-deficient cardiomyocytes, the NF-κB-dependent inflammatory response to LPS is hypersensitive; iASPP normally dampens NF-κB binding activity at promoters of pro-inflammatory cytokine genes.\",\n      \"method\": \"Human genetics (identifying PPP1R13L premature stop codon), NF-κB EMSA and ChIP on patient fibroblasts, siRNA knockdown of Ppp1r13l in murine cardiomyocytes, RNA sequencing of Ppp1r13l-deficient mouse hearts\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetic loss-of-function combined with NF-κB EMSA/ChIP mechanistic studies and mouse model, replicated across cell types and species\",\n      \"pmids\": [\"28069640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In cardiomyocyte-specific iASPP-deficient mice, loss of iASPP is sufficient to cause cardiac disorder; in keratinocyte-specific iASPP-deficient mice, loss of iASPP causes cutaneous disorder, delayed eyelid development, and impaired wound healing. Junctional iASPP in keratinocytes is critical for desmosome stabilization; its deficiency results in increased and disorganized cell migration and impaired cell adhesion.\",\n      \"method\": \"Cardiomyocyte-specific and keratinocyte-specific Cre/loxP iASPP knockout mice, desmosome integrity assays, cell migration and adhesion assays, wound healing models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic knockouts with defined mechanistic phenotypes in desmosome integrity and wound healing\",\n      \"pmids\": [\"29352264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Overexpression of PPP1R13L promotes p53 degradation via the proteasome, depletes active p65/RelA, and accelerates tumor formation driven by RAS/E1A, modulating both p53-dependent and p53-independent apoptosis pathways.\",\n      \"method\": \"Overexpression in primary MEFs (with/without p53); proteasome inhibitor (MG132) experiments; in vivo tumor formation assays\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic overexpression with proteasome inhibitor mechanistic dissection, single lab\",\n      \"pmids\": [\"19263435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"iASPP is identified as an ERK-primed GSK-3 substrate; in the presence of GSK-3, iASPP is targeted for degradation, linking KSHV LANA-mediated kinase dysregulation to iASPP stability.\",\n      \"method\": \"Protein microarray phosphorylation screen, cotransfection with GSK-3, proteasome-dependent degradation assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — microarray screen followed by cotransfection confirmation and degradation assay, single lab\",\n      \"pmids\": [\"26109723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CDK1 (cyclin-dependent kinase 1) physically interacts with iASPP protein; this interaction affects colorectal cancer cell proliferation and apoptosis through the p53 apoptosis pathway.\",\n      \"method\": \"GST pulldown assay, Co-immunoprecipitation, cell proliferation and apoptosis assays with CDK1 and iASPP manipulations\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — GST pulldown and Co-IP confirming direct interaction, single lab\",\n      \"pmids\": [\"29069733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"iASPP associates with the microtubule plus-end binding protein EB1 via an SxIP motif, and with Myosin-Ic (Myo1c). iASPP loss or mutation of its SxIP motif leads to defective microtubule capture at the cortex of mitotic cells, abnormal mitotic spindle positioning, and failure of cells to round up during mitosis due to defective cortical stiffness.\",\n      \"method\": \"Co-immunoprecipitation, SxIP motif mutagenesis, iASPP and Myo1c siRNA knockdown, atomic force microscopy for cortical stiffness, live imaging of mitotic spindle\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, site-specific mutagenesis, multiple functional readouts (stiffness, spindle positioning), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34705028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JNK-mediated phosphorylation of iASPP inhibits iASPP binding with AP1 components (such as JUND) via PXXP/SH3 domain-mediated interaction. iASPP regulates expression of a subset of p63 and AP1 target genes involved in skin differentiation and inflammation, acting as a tumor suppressor in RAS-driven, inflammation-promoted skin tumorigenesis.\",\n      \"method\": \"JNK phosphorylation assays, Co-IP of iASPP with JUND, iASPP loss-of-function in RAS/inflammation-driven mouse skin tumor model, gene expression profiling\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — kinase-substrate phosphorylation with Co-IP and in vivo mouse model, single lab\",\n      \"pmids\": [\"36261000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"iASPP suppresses KRAS-driven and inflammation-driven pancreatic cancer tumorigenesis and acinar-to-ductal metaplasia in a p53-independent manner; transcriptomic analysis shows iASPP deletion and p53 mutation overlap extensively in NF-κB and AP1-regulated inflammatory gene sets.\",\n      \"method\": \"Genetic mouse models (KRASG12D with iASPPΔ8/Δ8), in vitro ADM assays, syngeneic/nude mouse tumor models, RNA sequencing\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic double-mutant mouse models establishing epistatic relationship, multiple tumor models, transcriptomic mechanistic profiling\",\n      \"pmids\": [\"37270580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"iASPP interacts with NAF-1 (a NEET 2Fe-2S protein); peptide mapping and computational analysis localized the interaction to residues 764-778 of iASPP binding a surface groove of NAF-1. This iASPP-NAF-1 interaction is stimulated during apoptosis in cancer cells and is required for apoptosis activation.\",\n      \"method\": \"Peptide array screening, computational modeling, cell-based interaction assay, apoptosis inhibition assay with iASPP 764-780 peptide in cancer cells\",\n      \"journal\": \"Chemical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — peptide array and cell-based assay without full structural or Co-IP validation, single lab\",\n      \"pmids\": [\"30774867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Measles virus C protein specifically interacts with the p65-iASPP protein complex, as determined by affinity purification/mass spectrometry and protein complementation assay, potentially hijacking the cell death and innate immunity regulatory functions of this complex.\",\n      \"method\": \"Affinity purification coupled to mass spectrometry, protein complementation assay (PCA), bioluminescence resonance energy transfer (BRET)\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — AP-MS plus PCA/BRET orthogonal validation, single lab; functional consequence in viral context not fully established\",\n      \"pmids\": [\"33515806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"iASPP inhibits chemotherapy-induced senescence (TIS) by translocating to the nucleus in senescent cells (driven by NF-κBp65 transcriptional induction), where it binds p53 and NF-κBp65, inhibiting their transcriptional activation of p21 and SASP factors IL-6/IL-8, thereby preventing senescence and conferring drug resistance independently of apoptosis.\",\n      \"method\": \"iASPP knockdown in HCT116 and MCF-7 cells, xenograft model, Co-IP of iASPP with p53 and p65, reporter assays, senescence markers (SA-β-Gal, p21)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and reporter assays with functional senescence phenotype in vitro and in vivo, single lab\",\n      \"pmids\": [\"32005663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FHL2 is a binding partner of iASPP (identified by yeast two-hybrid screen and confirmed by Co-IP); FHL2 and iASPP co-localize in both nucleus and cytoplasm of leukemia cells. When FHL2 is knocked down, iASPP protein expression also decreases, and vice versa, suggesting mutual stabilization.\",\n      \"method\": \"Yeast two-hybrid screen, Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, Western blot\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid with Co-IP confirmation, single lab\",\n      \"pmids\": [\"28402264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NF-κB increases expression of iASPP through p65/p50 binding to a putative NF-κB-binding site in the iASPP promoter; hepatitis B virus X protein upregulates iASPP expression via NF-κB activation.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation, electrophoretic mobility shift assay (EMSA)\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus EMSA plus reporter assay establishing direct transcriptional regulation, multiple methods, single lab\",\n      \"pmids\": [\"20600029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"p53 and PPP1R13L form a negative feedback loop: p53 accumulation after DNA damage drives PPP1R13L expression (dependent on p53 target genes BAX and GADD45α), while PPP1R13L in turn inhibits p53 function. Proteasome inhibition leads to accumulation of both p53 and PPP1R13L.\",\n      \"method\": \"siRNA knockdown of p53, PPP1R13L, BAX, and GADD45α; Western blot, qPCR, proteasome inhibitor (MG132) treatment in human and mouse cells with varying p53 status\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — systematic siRNA epistasis across multiple cell lines with multiple pathway nodes, single lab\",\n      \"pmids\": [\"20840860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"iASPP phosphorylation at serine residues (which increases iASPP affinity toward p53) is significantly reduced following optic nerve axotomy in retinal ganglion cells (RGCs). iASPP knockdown exacerbates RGC death after axotomy; AAV-mediated iASPP overexpression promotes RGC survival and downregulates p53 activity and pro-apoptotic targets PUMA and Fas/CD95.\",\n      \"method\": \"siRNA knockdown, AAV-mediated overexpression, in vivo optic nerve axotomy model, phospho-specific Western blot, p53 target gene expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo gain/loss-of-function with mechanistic p53 pathway readouts, single lab\",\n      \"pmids\": [\"24714389\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"iASPP (PPP1R13L) is a multifunctional scaffolding protein and predicted PP1 regulatory subunit that inhibits p53 transcriptional activity by contacting the p53 DNA-binding domain and displacing the L1 loop (established by crystal structure), while also suppressing p63, p73, and NF-κB/RelA; it is phosphorylated by cyclin B1/CDK1 to drive nuclear entry and enhanced p53 inhibition, dephosphorylated via an iASPP-PP1 complex it assembles (requiring its noncanonical RNYF/SH3 motif), cleaved by caspases at SSLD294 to generate a more potent nuclear inhibitory fragment, and it acts outside apoptosis by binding Keap1 to stabilize Nrf2 and reduce ROS, binding VHL to stabilize HIF-1α, binding GRP78-competing E3 ligase RNF185 to regulate ER stress responses, binding TMCO1-targeting E3 ligase Gp78 to regulate Ca2+ homeostasis, interacting with desmoplakin and desmin at intercalated discs to maintain desmosome integrity, associating with EB1 via an SxIP motif and Myosin-Ic to regulate mitotic cortical stiffness and spindle positioning, and facilitating CEP55 dephosphorylation for cytokinetic abscission—collectively placing iASPP at the intersection of apoptosis, oxidative stress, ER homeostasis, Ca2+ signaling, cell division, and desmosomal integrity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PPP1R13L (iASPP) is an evolutionarily conserved oncoprotein and multifunctional scaffold whose canonical role is inhibition of p53-dependent apoptosis [#0]. It binds the p53 DNA-binding domain and proline-rich region, and the crystal structure of the p53-iASPP complex shows it displaces the p53 L1 loop to reshape DNA-binding site selectivity along a surface overlapping the HPV E6 footprint [#1, #15]. iASPP function is governed by tightly regulated subcellular partitioning and post-translational control: cyclin B1/CDK1 phosphorylation disrupts iASPP dimerization, drives nuclear entry of the monomer, and exposes its p53-binding sites to enhance p53 inhibition [#7], while caspase cleavage at SSLD294 generates an 80 kDa nuclear fragment that inhibits p53 and RelA/p65 more potently than the full-length protein [#13]. iASPP also acts as a noncanonical PP1-targeting subunit, engaging PP1 through an RNYF motif in its SH3 domain that is required for p53 inhibition [#4]. Its repressive activity extends beyond p53 to the p53-family transcription factors p63 and p73 and to NF-\\u03baB/RelA, integrating control of epithelial stratification, inflammation, and apoptosis [#5, #8, #21]. Independently of apoptosis, iASPP stabilizes stress-response and homeostatic effectors by competing with E3-ligase or adaptor partners: it competes with Nrf2 for Keap1 to suppress Nrf2 ubiquitination and reduce ROS [#10], binds VHL to block HIF-1\\u03b1 degradation [#19], competes with Gp78 to protect the Ca2+ channel TMCO1 [#18], and competes with GRP78 for the ER-resident ligase RNF185 to modulate the unfolded-protein response [#20]. During cell division, iASPP couples to the cytoskeleton and mitotic machinery: it associates with EB1 via an SxIP motif and with Myosin-Ic to control cortical stiffness and spindle positioning [#26], and targets PP1 to dephosphorylate CEP55 for cytokinetic abscission [#14]. At desmosomes, iASPP binds desmoplakin and desmin to maintain intercalated-disc integrity [#9]. Loss-of-function PPP1R13L mutation causes a human cardio-cutaneous syndrome with hypersensitive NF-\\u03baB-driven inflammation, and iASPP-deficient mice develop ARVC-like cardiac disease and cutaneous defects [#9, #21, #22].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established iASPP as a conserved inhibitor of p53 whose loss triggers p53-dependent apoptosis, defining it as an oncoprotein rather than a passive binding partner.\",\n      \"evidence\": \"RNAi in C. elegans and antisense RNA in human cells plus oncogenic transformation assays\",\n      \"pmids\": [\"12524540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular contact surface on p53\", \"Did not address p53-independent roles\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved that iASPP has cytoplasmic and nuclear isoforms, framing localization control as central to its activity.\",\n      \"evidence\": \"Subcellular fractionation, immunofluorescence and functional p53/apoptosis assays on long and short isoforms\",\n      \"pmids\": [\"15489900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the signals or modifications driving nuclear translocation\", \"Isoform-specific functional differences beyond localization unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the p53 proline-rich region as an additional iASPP contact and linked the codon-72 polymorphism to differential apoptotic output.\",\n      \"evidence\": \"Binding assays with p53 PRR and apoptosis assays in polymorphic variants\",\n      \"pmids\": [\"16964264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic basis of selectivity not yet resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed that stress-induced p53 Ser46 phosphorylation and Pin1 actively dissociate the iASPP-p53 complex, establishing a regulated switch from inhibition to apoptosis.\",\n      \"evidence\": \"Co-IP, ChIP, reporter assays and Pin1-binding mutagenesis\",\n      \"pmids\": [\"17906639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct iASPP residues targeted by this switch not mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked iASPP overexpression to proteasomal p53 degradation and RAS/E1A-driven tumorigenesis, extending its action to p53 turnover.\",\n      \"evidence\": \"Overexpression in MEFs with MG132 and in vivo tumor formation\",\n      \"pmids\": [\"19263435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which iASPP promotes p53 degradation not defined\", \"No direct ligase identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Embedded iASPP in transcriptional feedback loops with both p53 and NF-\\u03baB, showing it is itself an inducible node responsive to DNA damage and viral signals.\",\n      \"evidence\": \"siRNA epistasis (p53/BAX/GADD45\\u03b1), ChIP, EMSA and reporter assays; HBx induction via NF-\\u03baB\",\n      \"pmids\": [\"20840860\", \"20600029\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative dynamics of the feedback loops not modeled\", \"Promoter occupancy in physiological settings limited\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified iASPP as a noncanonical PP1-targeting subunit and broadened its transcriptional targets to p63 and NF-\\u03baB/RelA, revealing scaffold and phosphatase-recruitment functions beyond p53.\",\n      \"evidence\": \"RNYF/F815A mutagenesis with GST pulldown; knockout mouse with keratinocyte phenotypes and Co-IP for p63/RelA\",\n      \"pmids\": [\"21998301\", \"21930934\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PP1 substrates recruited by iASPP not yet enumerated\", \"Structural basis of the noncanonical RNYF/PP1 interface unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected iASPP to mitotic survival via separase activation, an early indication of p53-independent roles in cell division.\",\n      \"evidence\": \"Gain/loss-of-function in ovarian cancer cells with separase activity and mitotic catastrophe assays\",\n      \"pmids\": [\"21926165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between iASPP and separase not established\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined cyclin B1/CDK1 phosphorylation as the switch that disassembles iASPP dimers, drives nuclear entry, and exposes p53-binding sites, mechanistically coupling cell-cycle state to p53 inhibition.\",\n      \"evidence\": \"Phosphorylation, dimerization and nuclear fractionation assays with CDK1 inhibition; melanoma metastasis correlation\",\n      \"pmids\": [\"23623661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosite residues and their stoichiometry only partly defined\", \"Phosphatase reversing this in vivo not identified here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed apoptosis-independent roles in autophagy and neuronal survival, showing iASPP modulates Atg complex assembly and that its phospho-state tracks injury-induced p53 activity.\",\n      \"evidence\": \"siRNA with LC3 lipidation and Atg5-Atg12/Atg16L1 Co-IP; in vivo optic nerve axotomy with phospho-specific blotting\",\n      \"pmids\": [\"24777476\", \"24714389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct iASPP-Atg interaction surface not mapped\", \"Kinase/phosphatase controlling RGC iASPP phospho-state unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established structural roles at desmosomes and additional regulators of apoptotic competence, broadening iASPP from a transcriptional inhibitor to a cytoarchitectural and acetyltransferase-stabilizing scaffold.\",\n      \"evidence\": \"Reciprocal Co-IP with desmoplakin/desmin and knockout mouse with ARVC-like phenotype; p300/CBP ubiquitination and caspase cleavage-site (SSLD294) mutagenesis with fractionation\",\n      \"pmids\": [\"25691752\", \"25675294\", \"26646590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How desmosomal and nuclear pools are partitioned unclear\", \"Functional impact of the 80 kDa fragment in vivo not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified the iASPP-Keap1-Nrf2 axis and a human loss-of-function disease, linking iASPP to oxidative-stress control, NF-\\u03baB-driven inflammation, and a defined cardio-cutaneous syndrome.\",\n      \"evidence\": \"DLT-motif competitive binding and ubiquitination assays for Keap1/Nrf2; human PPP1R13L stop-codon genetics with NF-\\u03baB EMSA/ChIP and mouse models\",\n      \"pmids\": [\"29033244\", \"28069640\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific balance between oncogenic and tumor-suppressive functions unresolved\", \"How a single locus produces both cardiac and cutaneous phenotypes only partly explained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined iASPP as a PP1-CEP55 targeting factor required for cytokinetic abscission and identified additional protein partners, deepening its mitotic and homeostatic roles.\",\n      \"evidence\": \"Affinity purification/Co-IP with CEP55-Ser436 dephosphorylation and cytokinesis phenotypes; cell-type-specific knockout mice; NAF-1 peptide mapping\",\n      \"pmids\": [\"29743530\", \"29352264\", \"30774867\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NAF-1 interaction lacks Co-IP/structural confirmation\", \"Coordination of mitotic versus interphase iASPP pools unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the atomic mechanism of p53 inhibition: iASPP displaces the p53 L1 loop to alter DNA-binding site selectivity, distinguishing it from other p53-binding regulators.\",\n      \"evidence\": \"X-ray crystallography of the p53-iASPP complex with genome-wide binding-site analysis\",\n      \"pmids\": [\"31395738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures of iASPP with p63/p73 or RelA not determined\", \"How phosphorylation alters the structural interface not visualized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanded the competitive-binding paradigm to VHL/HIF-1\\u03b1, Gp78/TMCO1, and RNF185/GRP78, establishing iASPP as a general antagonist of E3-ligase substrate recognition controlling hypoxia, Ca2+, and ER-stress responses.\",\n      \"evidence\": \"Competitive Co-IP and ubiquitination assays with functional HIF-1\\u03b1, Ca2+, and UPR readouts plus in vivo tumor models; EB1/Myo1c SxIP work on cortical mechanics\",\n      \"pmids\": [\"35169254\", \"35121659\", \"36380064\", \"34705028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether one iASPP molecule integrates these axes or distinct pools act separately is unknown\", \"Determinants of partner selectivity among competing E3 systems unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated a context-dependent tumor-suppressive role in KRAS- and inflammation-driven cancers acting through NF-\\u03baB/AP1 gene sets, sharpening the dual oncogene/tumor-suppressor model.\",\n      \"evidence\": \"Genetic KRASG12D;iASPP-deletion mouse models with ADM assays and RNA-seq; JNK-AP1/JUND phosphoregulation in skin tumorigenesis\",\n      \"pmids\": [\"37270580\", \"36261000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular determinant switching iASPP between oncogenic and suppressive output not identified\", \"Relationship to its p53-inhibitory function in these tissues unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how the multiple post-translational switches and competing partner pools are coordinated to assign iASPP to a specific function in a given cell state.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model relating phosphorylation, cleavage, and localization to partner choice\", \"Full PP1 substrate repertoire targeted by iASPP undefined\", \"Structural basis of non-p53 inhibitory complexes lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5, 8, 15, 17, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 10, 14, 18, 19, 20]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 9, 14, 26]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 7, 13, 15, 31]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9, 22, 26]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [18, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 8, 13, 29]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 7, 14, 26]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [10, 18, 20]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 19, 21]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 5, 15]}\n    ],\n    \"complexes\": [\"iASPP-PP1 complex\", \"desmosome/intercalated disc\"],\n    \"partners\": [\"TP53\", \"RELA\", \"KEAP1\", \"VHL\", \"PPP1CA\", \"CEP55\", \"DSP\", \"MAPRE1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}