{"gene":"PPRC1","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":2008,"finding":"Stable shRNA-mediated knockdown of PRC (PPRC1) in U2OS cells caused severe inhibition of respiratory chain function, reduced expression of respiratory protein subunits from complexes I, II, III, and IV, markedly lower complex I and IV enzyme levels, diminished mitochondrial ATP production, and proliferation of abnormal mitochondria devoid of organized cristae, establishing PRC as required for mitochondrial respiratory function and integrity.","method":"Lentiviral shRNA knockdown (two independent shRNAs), respiratory enzyme assays, mitochondrial ATP production measurement, microarray gene expression analysis, electron microscopy of mitochondrial morphology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — two independent shRNA lines with concordant phenotypes, multiple orthogonal functional readouts","pmids":["19036724"],"is_preprint":false},{"year":2013,"finding":"PRC (PPRC1)-dependent stress program is activated during apoptosis and premature senescence; PRC and its target genes (IL1α, SPRR2D, SPRR2F) are rapidly induced by menadione (apoptosis via ROS) and by topoisomerase I inhibitor SN-38 (premature senescence). Antioxidant N-acetylcysteine blocked menadione-induced PRC induction, and c-MYC was coordinately induced with PRC under all stress conditions tested.","method":"Pharmacological induction (menadione, SN-38, meclizine), antioxidant rescue experiments, gene expression assays, senescence-associated β-galactosidase staining, siRNA knockdown of c-MYC","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — clean loss-of-function and pharmacological rescue with defined cellular phenotypes, single lab","pmids":["23364789"],"is_preprint":false},{"year":2016,"finding":"PRC (PPRC1) and c-MYC act in concert through Akt-GSK-3 signaling to reprogram gene expression in response to mitochondrial stress. GSK-3 phosphorylation of two serine residues in the PRC C-terminal domain reduces PRC steady-state expression; mutation of these GSK-3 sites markedly increased PRC protein levels. CCCP-induced mitochondrial uncoupling activated Akt, which phospho-inactivated GSK-3β, thereby stabilizing PRC post-translationally. c-MYC inhibition blocked PRC induction, and Akt inhibition blocked both c-MYC and PRC induction.","method":"GSK-3 site mutagenesis, pharmacological inhibitors (10058-F4, AZD2858, MK-2206), c-MYC siRNA silencing, protein half-life measurements, Akt inhibitor experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis of phosphorylation sites combined with pharmacological epistasis and siRNA, multiple orthogonal methods in single lab","pmids":["27789709"],"is_preprint":false},{"year":2020,"finding":"PDE5 inhibition by sildenafil induces PRC (PPRC1) expression through a cAMP- and CREB-dependent mechanism, independently of Akt3. PRC induction by sildenafil rescued mitochondrial dysfunction (uncoupled oxygen consumption, mitochondrial DNA content, VDAC expression) caused by Akt3 depletion and promoted angiogenesis, demonstrating that PRC can functionally substitute for PGC-1α during mitochondrial stress.","method":"Akt3 siRNA depletion, sildenafil treatment, oxygen consumption assays, mitochondrial DNA quantification, VDAC protein expression, tube formation angiogenesis assays, cAMP pathway analysis, CREB reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (genetic and pharmacological) with functional readouts, single lab","pmids":["33087445"],"is_preprint":false},{"year":2013,"finding":"PRC (PPRC1) overexpression in HUVECs suppresses LPS-induced endothelial inflammation by inhibiting NF-κB transcriptional activity, reducing VCAM-1 and E-selectin expression, attenuating monocyte adhesion, and protecting mitochondrial metabolic function.","method":"Overexpression in HUVECs, NF-κB reporter assay, VCAM-1/E-selectin expression assays, monocyte adhesion assay, mitochondrial function measurement","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — overexpression with multiple functional readouts but single lab, no endogenous loss-of-function","pmids":["23954632"],"is_preprint":false},{"year":2014,"finding":"PRC (PPRC1) cooperates with STAT6 to induce M2 microglia polarization; PRC overexpression increased arginase-1 (Arg1), Fizz1 (Retnla), and Ym1 (Chi3l3) expression, while PRC silencing attenuated M2 polarization markers.","method":"PRC overexpression and siRNA silencing in microglia, qPCR for M2 marker genes, co-immunoprecipitation or co-activation assay with STAT6","journal":"Journal of molecular neuroscience","confidence":"Low","confidence_rationale":"Tier 3 — single lab, limited mechanistic detail on STAT6 interaction, no biochemical confirmation of direct interaction","pmids":["24838382"],"is_preprint":false},{"year":2015,"finding":"Heterozygous Pprc1 knockout male mice fed a high-fat diet were resistant to diet-induced obesity with decreased adipose tissue due to elevated energy expenditure. In skeletal muscle of Pprc1+/- mice, Pprc1 showed haplo-insufficiency with down-regulation of Pgc1b and Pgc1a, while adipose tissue showed compensatory upregulation of other PGC-1 family members and respiratory chain genes, establishing Pprc1's role in controlling mitochondrial gene expression and energy metabolic processes in vivo.","method":"Heterozygous knockout mouse model, high-fat diet challenge, metabolic phenotyping (energy expenditure, adipose tissue mass), qPCR for mitochondrial and PGC-1 family genes","journal":"Endocrine journal","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genetic model with multiple metabolic readouts, single lab","pmids":["25994039"],"is_preprint":false},{"year":2020,"finding":"PPRC1 expression levels directly correlate with expression of mitochondrial proteins TFAM and SDHA in human dermal fibroblasts across multiple cell lines, whereas PGC-1α expression does not, suggesting PPRC1 is a functionally active regulator of mitochondrial biogenesis in fibroblasts. PGC-1α knockdown led to a slight decrease in TFAM protein and mtDNA-encoded MT-CO2, supporting cooperative roles for PGC-1α and PPRC1.","method":"Gene expression correlation across 10 cell lines, siRNA knockdown of PGC-1α, protein expression analysis (TFAM, SDHA, MT-CO2)","journal":"Genetics and molecular biology","confidence":"Low","confidence_rationale":"Tier 3 — correlative expression analysis with limited mechanistic knockdown of PPRC1 itself","pmids":["32639509"],"is_preprint":false},{"year":2021,"finding":"COL5A1 overexpression in glioblastoma upregulates PPRC1 and downstream ESM1, promoting cell mobility, metastatic ability, and actin polymerization, placing PPRC1 as an intermediate transcription factor in the COL5A1-PPRC1-ESM1 signaling axis in GBM.","method":"Transcriptomics dataset from COL5A1 overexpression, IPA pathway analysis, functional validation of cell mobility and actin polymerization","journal":"Cell death discovery","confidence":"Low","confidence_rationale":"Tier 3-4 — pathway placement based on transcriptomics and IPA prediction with limited direct mechanistic validation of PPRC1's role","pmids":["34702798"],"is_preprint":false},{"year":2025,"finding":"Eugenol inhibits AML cell growth and promotes apoptosis through the mitochondrial pathway by downregulating PPRC1 at both protein and mRNA levels and reducing mitochondrial membrane potential, establishing PPRC1 as a pro-survival regulator of mitochondrial biogenesis in AML cells.","method":"Eugenol treatment of AML cell lines and primary patient cells, apoptosis assays, qPCR and western blot for PPRC1, mitochondrial membrane potential measurement, cytarabine-resistant cell testing","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2-3 — pharmacological target engagement with multiple cell models and orthogonal readouts, but no direct PPRC1 loss-of-function rescue","pmids":["39996733"],"is_preprint":false},{"year":2021,"finding":"A novel heterozygous point mutation in PPRC1 (c.2902C>T, p.Thr958Ile) segregated with premature ovarian failure in a Chinese family. In vitro expression of PPRC1 in COV434 granulosa cells suggested PPRC1 is involved in regulating granulosa cell apoptosis but not senescence.","method":"Whole exome sequencing, Sanger sequencing, pedigree analysis, PPRC1 overexpression in granulosa cells, apoptosis assay, senescence staining","journal":"The journal of gene medicine","confidence":"Low","confidence_rationale":"Tier 3 — single family pedigree, limited in vitro mechanistic follow-up","pmids":["33818872"],"is_preprint":false}],"current_model":"PPRC1 (PRC/PGC-1-related coactivator) is a growth-regulated transcriptional coactivator that is essential for mitochondrial respiratory chain gene expression and biogenesis; it is post-translationally stabilized through an Akt-GSK-3 signaling axis in response to mitochondrial stress, acts in concert with c-MYC to reprogram gene expression during cellular stress (apoptosis, senescence, metabolic challenge), and suppresses NF-κB-driven endothelial inflammation, with in vivo evidence from heterozygous knockout mice confirming its role in energy expenditure and metabolic regulation."},"narrative":{"teleology":[{"year":2008,"claim":"The foundational question of whether PPRC1 is required for mitochondrial function was resolved: PPRC1 loss of function causes comprehensive respiratory chain failure and mitochondrial structural disorganization, establishing it as an essential regulator of mitochondrial biogenesis.","evidence":"Lentiviral shRNA knockdown with two independent hairpins in U2OS cells, measuring respiratory enzyme activity, ATP production, gene expression by microarray, and mitochondrial ultrastructure by electron microscopy","pmids":["19036724"],"confidence":"High","gaps":["No identification of specific transcription factor partners through which PPRC1 drives respiratory gene expression","In vivo requirement not yet tested","Mechanism of PPRC1 regulation itself unknown"]},{"year":2013,"claim":"PPRC1 was shown to be a stress-responsive gene activated during apoptosis and premature senescence through ROS-dependent signaling, revealing that its function extends beyond basal mitochondrial maintenance to cellular stress adaptation, with c-MYC coordinately induced alongside PPRC1.","evidence":"Pharmacological stress induction (menadione, SN-38, meclizine) with antioxidant rescue (NAC) and c-MYC siRNA in U2OS cells","pmids":["23364789"],"confidence":"Medium","gaps":["Direct transcriptional mechanism linking ROS to PPRC1 promoter activation not defined","Whether c-MYC directly binds the PPRC1 promoter or acts indirectly not established","Single laboratory findings"]},{"year":2013,"claim":"PPRC1 was identified as a suppressor of NF-κB-mediated endothelial inflammation, broadening its functional scope beyond mitochondrial biogenesis to inflammatory signaling.","evidence":"PPRC1 overexpression in HUVECs with LPS stimulation, NF-κB reporter assays, VCAM-1/E-selectin expression, and monocyte adhesion assays","pmids":["23954632"],"confidence":"Medium","gaps":["No endogenous loss-of-function experiment to confirm anti-inflammatory role","Mechanism by which PPRC1 inhibits NF-κB activity not defined","Limited to overexpression system in a single lab"]},{"year":2015,"claim":"In vivo genetic evidence confirmed PPRC1's non-redundant role in energy metabolism: heterozygous knockout mice showed elevated energy expenditure and resistance to diet-induced obesity, with tissue-specific haploinsufficiency effects on PGC-1 family members.","evidence":"Pprc1 heterozygous knockout mice on high-fat diet with metabolic phenotyping and gene expression profiling in skeletal muscle and adipose tissue","pmids":["25994039"],"confidence":"Medium","gaps":["Complete knockout phenotype not reported (likely embryonic lethal but not characterized)","Tissue-specific conditional knockout not performed","Mechanism of compensatory PGC-1 family upregulation in adipose tissue unknown"]},{"year":2016,"claim":"The post-translational regulation of PPRC1 was elucidated: GSK-3 phosphorylates two C-terminal serine residues to destabilize PPRC1, while mitochondrial stress activates the Akt–GSK-3β axis to stabilize PPRC1 protein, with c-MYC acting upstream in this pathway.","evidence":"GSK-3 site mutagenesis, pharmacological epistasis with Akt (MK-2206) and GSK-3 (AZD2858) inhibitors, c-MYC siRNA, and protein half-life measurements after CCCP-induced mitochondrial uncoupling","pmids":["27789709"],"confidence":"High","gaps":["The E3 ubiquitin ligase mediating GSK-3-dependent PPRC1 degradation not identified","Whether additional kinases regulate PPRC1 stability is unknown","Structural basis for GSK-3 recognition of PPRC1 not determined"]},{"year":2020,"claim":"An alternative pathway for PPRC1 induction was identified through PDE5 inhibition: sildenafil induces PPRC1 via cAMP–CREB signaling, independently of Akt3, and PPRC1 can functionally rescue mitochondrial defects caused by Akt3 depletion.","evidence":"Sildenafil treatment of Akt3-depleted endothelial cells with oxygen consumption, mtDNA, and VDAC assays; CREB reporter and cAMP pathway analysis","pmids":["33087445"],"confidence":"Medium","gaps":["Direct CREB binding to PPRC1 promoter not demonstrated by ChIP","Whether PPRC1 fully substitutes for PGC-1α in vivo not tested","Single laboratory"]},{"year":2021,"claim":"A heterozygous missense mutation in PPRC1 (p.Thr958Ile) was linked to familial premature ovarian failure, suggesting a role for PPRC1 in ovarian granulosa cell survival.","evidence":"Whole exome sequencing and Sanger validation in a single Chinese family; PPRC1 overexpression in COV434 granulosa cells with apoptosis assays","pmids":["33818872"],"confidence":"Low","gaps":["Single family pedigree without replication in independent cohorts","No demonstration that the Thr958Ile variant causes loss of function biochemically","Granulosa cell phenotype based on overexpression, not endogenous mutation modeling"]},{"year":2025,"claim":"Pharmacological downregulation of PPRC1 by eugenol in AML cells induced mitochondrial depolarization and apoptosis, supporting PPRC1 as a pro-survival factor that maintains mitochondrial integrity in leukemia.","evidence":"Eugenol treatment of AML cell lines and primary patient cells with PPRC1 mRNA/protein quantification, mitochondrial membrane potential assays, and apoptosis measurement","pmids":["39996733"],"confidence":"Medium","gaps":["No direct PPRC1 loss-of-function rescue to confirm PPRC1 as the critical eugenol target","Whether PPRC1 dependence is specific to AML or general across cancers is unknown","Eugenol has pleiotropic effects; PPRC1 may be a secondary target"]},{"year":null,"claim":"Key unresolved questions include the identity of the E3 ligase mediating GSK-3-dependent PPRC1 degradation, the direct transcription factor partners through which PPRC1 activates respiratory chain gene promoters, and whether complete PPRC1 loss is embryonic lethal.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural information for PPRC1 or its coactivator domains","Genome-wide direct target identification by ChIP-seq not performed","Conditional tissue-specific knockout models lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,3,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,9]}],"complexes":[],"partners":["MYC","GSK3B","AKT1"],"other_free_text":[]},"mechanistic_narrative":"PPRC1 is a growth-regulated transcriptional coactivator that functions as a critical regulator of mitochondrial biogenesis, respiratory chain gene expression, and cellular stress responses. Knockdown of PPRC1 severely impairs respiratory chain function, reduces expression of complexes I–IV, diminishes mitochondrial ATP production, and causes proliferation of abnormal mitochondria lacking organized cristae [PMID:19036724]. PPRC1 protein stability is controlled post-translationally through an Akt–GSK-3β signaling axis: GSK-3 phosphorylation of C-terminal serine residues promotes PPRC1 degradation, while mitochondrial stress activates Akt to phospho-inactivate GSK-3β and stabilize PPRC1, acting in concert with c-MYC to reprogram gene expression during apoptosis and premature senescence [PMID:27789709, PMID:23364789]. In vivo, heterozygous Pprc1 knockout mice exhibit elevated energy expenditure and resistance to diet-induced obesity, with haploinsufficiency causing downregulation of PGC-1α and PGC-1β in skeletal muscle, confirming a non-redundant role in systemic energy metabolism [PMID:25994039]."},"prefetch_data":{"uniprot":{"accession":"Q5VV67","full_name":"Peroxisome proliferator-activated receptor gamma coactivator-related protein 1","aliases":["PGC-1-related coactivator","PRC"],"length_aa":1664,"mass_kda":177.5,"function":"Acts as a coactivator during transcriptional activation of nuclear genes related to mitochondrial biogenesis and cell growth. Involved in the transcription coactivation of CREB and NRF1 target genes","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q5VV67/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PPRC1","classification":"Common Essential","n_dependent_lines":648,"n_total_lines":1208,"dependency_fraction":0.5364238410596026},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PPRC1","total_profiled":1310},"omim":[{"mim_id":"617462","title":"PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA, COACTIVATOR-RELATED PROTEIN 1; PPRC1","url":"https://www.omim.org/entry/617462"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PPRC1"},"hgnc":{"alias_symbol":["PRC","KIAA0595","MGC74642"],"prev_symbol":[]},"alphafold":{"accession":"Q5VV67","domains":[{"cath_id":"3.30.70.330","chopping":"1524-1623","consensus_level":"medium","plddt":83.5803,"start":1524,"end":1623}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VV67","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VV67-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VV67-F1-predicted_aligned_error_v6.png","plddt_mean":41.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPRC1","jax_strain_url":"https://www.jax.org/strain/search?query=PPRC1"},"sequence":{"accession":"Q5VV67","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5VV67.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5VV67/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VV67"}},"corpus_meta":[{"pmid":"16339279","id":"PMC_16339279","title":"Up-regulation 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with PR(B) but interferes in PR(B)-DNA binding.","date":"1997","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9408082","citation_count":53,"is_preprint":false},{"pmid":"15496525","id":"PMC_15496525","title":"The PRC-barrel domain of the ribosome maturation protein RimM mediates binding to ribosomal protein S19 in the 30S ribosomal subunits.","date":"2004","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/15496525","citation_count":51,"is_preprint":false},{"pmid":"29138488","id":"PMC_29138488","title":"Structural basis of adaptor-mediated protein degradation by the tail-specific PDZ-protease Prc.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29138488","citation_count":42,"is_preprint":false},{"pmid":"12429060","id":"PMC_12429060","title":"The PRC-barrel: a widespread, conserved domain shared by photosynthetic reaction center subunits and proteins of RNA metabolism.","date":"2002","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/12429060","citation_count":42,"is_preprint":false},{"pmid":"16000715","id":"PMC_16000715","title":"Prc protease promotes mucoidy in mucA mutants of Pseudomonas aeruginosa.","date":"2005","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/16000715","citation_count":42,"is_preprint":false},{"pmid":"22702647","id":"PMC_22702647","title":"ROS-scavenger and radioprotective efficacy of the new PrC-210 aminothiol.","date":"2012","source":"Radiation research","url":"https://pubmed.ncbi.nlm.nih.gov/22702647","citation_count":41,"is_preprint":false},{"pmid":"23966131","id":"PMC_23966131","title":"Spatial and stimulus-type tuning in the LEC, MEC, POR, PrC, CA1, and CA3 during spontaneous item recognition 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Pseudomonas wenzhouensis A20, From Animal Farm Sewage.","date":"2021","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34975778","citation_count":2,"is_preprint":false},{"pmid":"39287400","id":"PMC_39287400","title":"In vivo and in vitro analyses of the role of the Prc protease in inducing mucoidy in Pseudomonas aeruginosa.","date":"2024","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/39287400","citation_count":1,"is_preprint":false},{"pmid":"31738662","id":"PMC_31738662","title":"Impact of the PrC-210 Radioprotector Molecule on Cancer Deaths in p53-Deficient Mice.","date":"2019","source":"Radiation research","url":"https://pubmed.ncbi.nlm.nih.gov/31738662","citation_count":1,"is_preprint":false},{"pmid":"30958087","id":"PMC_30958087","title":"Specific Reconstruction on pRC Plasmid to Facilitate Its Universal Chromosomal Integration in Different Ralstonia solanacearum Species Complex Strains.","date":"2019","source":"Molecular 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I. Structuring of recombinant from human insulin gene and ammalian expression vector PRC/CMV].","date":"1997","source":"Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae","url":"https://pubmed.ncbi.nlm.nih.gov/10453511","citation_count":1,"is_preprint":false},{"pmid":"24818420","id":"PMC_24818420","title":"[Polymorphism analysis on the genotypes of circumsporozoite protein of Plasmodium vivax with PRC-RFLP].","date":"2013","source":"Zhongguo ji sheng chong xue yu ji sheng chong bing za zhi = Chinese journal of parasitology & parasitic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/24818420","citation_count":1,"is_preprint":false},{"pmid":"37649762","id":"PMC_37649762","title":"Tachycardia and fever after packed red cell (PRC) infusion: A case report.","date":"2023","source":"Journal of family medicine and primary care","url":"https://pubmed.ncbi.nlm.nih.gov/37649762","citation_count":0,"is_preprint":false},{"pmid":"33818872","id":"PMC_33818872","title":"A novel PPRC1 point mutation in a Chinese family with premature ovarian failure: A case study.","date":"2021","source":"The journal of gene medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33818872","citation_count":0,"is_preprint":false},{"pmid":"39142656","id":"PMC_39142656","title":"Significant Reduction of Radiation-Induced Death in Mice Treated with PrC-210 and G-CSF after Irradiation.","date":"2024","source":"Radiation research","url":"https://pubmed.ncbi.nlm.nih.gov/39142656","citation_count":0,"is_preprint":false},{"pmid":"38854061","id":"PMC_38854061","title":"In vivo and in vitro analysis of the role of the Prc protease in inducing mucoidy in Pseudomonas aeruginosa.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38854061","citation_count":0,"is_preprint":false},{"pmid":"40907937","id":"PMC_40907937","title":"Periplasmic Serine Protease Prc is Responsible for Amyloid Subunit CsgA Degradation and Proteostasis in Escherichia coli.","date":"2025","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/40907937","citation_count":0,"is_preprint":false},{"pmid":"40434399","id":"PMC_40434399","title":"The PDZ Domain-Containing Protein Prc Is Involved in Virulence and Stress Tolerance in the Poplar Canker Bacterium Lonsdalea populi.","date":"2025","source":"Phytopathology","url":"https://pubmed.ncbi.nlm.nih.gov/40434399","citation_count":0,"is_preprint":false},{"pmid":"41684060","id":"PMC_41684060","title":"A new sensitive derivatization assay of PrC-210 in plasma and tissues using liquid chromatography coupled with tandem mass spectrometry.","date":"2026","source":"Bioanalysis","url":"https://pubmed.ncbi.nlm.nih.gov/41684060","citation_count":0,"is_preprint":false},{"pmid":"18726475","id":"PMC_18726475","title":"Inhibition of metastasis to lung of a human nasopharyngeal carcinoma cell line CNE- 2L2 transfected with pRc/ CMV-antisense 6A8 cDNA in nude mice.","date":"1999","source":"Science in China. Series C, Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/18726475","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.19.677292","title":"Transcriptional cofactor AtSDR4L and its paralog DIG2 repress somatic embryogenesis during post-embryonic development in Arabidopsis","date":"2025-09-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.19.677292","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.10.637455","title":"Polycomb group proteins protect latent Kaposi sarcoma-associated herpesvirus from episome clearance and HUSH-dependent chromatin silencing","date":"2025-02-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.10.637455","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.14.688451","title":"Polycomb Repressive Complexes 1 and 2 are recruited independently to pericentromeric heterochromatin in response to hypomethylation in mouse embryonic stem cells","date":"2025-11-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.14.688451","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.05.686712","title":"A Minimal Plasma Proteome-Based Biomarker Panel for Accurate Prostate Cancer Diagnosis","date":"2025-11-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.05.686712","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.05.22.595443","title":"Ellagic acid: a potential inhibitor of enhancer of zeste homolog-2 and protein arginine methyltransferase-5","date":"2024-05-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.05.22.595443","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.24.678279","title":"Phase resetting in human stem cell derived cardiomyocytes explains complex cardiac arrhythmias","date":"2025-09-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.24.678279","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.13.681825","title":"Epileptic encephalopathy-related Kv2.1 mutants impair channel clustering and membrane distribution but not neuronal excitability","date":"2025-10-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.13.681825","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.28.25334683","title":"Predicting 10-year Major Adverse Cardiac Events Using Multi-Source Modalities with XGBoost: Establishing a Baseline for Multimodal Fusion in Cardiac Risk Assessment","date":"2025-08-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.28.25334683","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.29.25332360","title":"segcsvd<sub>PVS</sub>: A convolutional neural network-based tool for quantification of enlarged perivascular spaces (PVS) on T1-weighted images","date":"2025-07-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.29.25332360","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.09.632091","title":"A Mean Field Theory for Pulse-Coupled Oscillators based on the Spike Time Response Curve","date":"2025-01-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.09.632091","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.10.658892","title":"Impaired envelope integrity in the absence of SanA is linked to increased Lipid II availability and an imbalance of FtsI and FtsW activities","date":"2025-06-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.10.658892","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.25.630354","title":"Periplasmic serine protease Prc is responsible for amyloid subunit CsgA degradation and proteostasis in<i>Escherichia coli</i>","date":"2024-12-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.25.630354","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.15.676241","title":"Molecular structure of the ESCRT III-based archaeal CdvAB cell division machinery","date":"2025-09-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.15.676241","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.16.665154","title":"Correlated protein-RNA associations reveal a requirement for HNRNPU in long-range Polycomb recruitment by the lncRNAs <i>Airn</i>, <i>Kcnq1ot1</i>, and <i>Xist</i>","date":"2025-07-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.16.665154","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46613,"output_tokens":3110,"usd":0.093244},"stage2":{"model":"claude-opus-4-6","input_tokens":6356,"output_tokens":2526,"usd":0.142395},"total_usd":0.235639,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about PPRC1 (PGC-1-related coactivator, also known as PRC), the human/mammalian transcriptional coactivator involved in mitochondrial biogenesis. I must distinguish this from bacterial Prc protease papers, plant PRC papers, and other symbol collisions.\n\nThe relevant PPRC1 papers are: 6, 16, 24, 31, 34, 39, 40, 53, 58, 61, 70.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"Stable shRNA-mediated knockdown of PRC (PPRC1) in U2OS cells caused severe inhibition of respiratory chain function, reduced expression of respiratory protein subunits from complexes I, II, III, and IV, markedly lower complex I and IV enzyme levels, diminished mitochondrial ATP production, and proliferation of abnormal mitochondria devoid of organized cristae, establishing PRC as required for mitochondrial respiratory function and integrity.\",\n      \"method\": \"Lentiviral shRNA knockdown (two independent shRNAs), respiratory enzyme assays, mitochondrial ATP production measurement, microarray gene expression analysis, electron microscopy of mitochondrial morphology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two independent shRNA lines with concordant phenotypes, multiple orthogonal functional readouts\",\n      \"pmids\": [\"19036724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PRC (PPRC1)-dependent stress program is activated during apoptosis and premature senescence; PRC and its target genes (IL1α, SPRR2D, SPRR2F) are rapidly induced by menadione (apoptosis via ROS) and by topoisomerase I inhibitor SN-38 (premature senescence). Antioxidant N-acetylcysteine blocked menadione-induced PRC induction, and c-MYC was coordinately induced with PRC under all stress conditions tested.\",\n      \"method\": \"Pharmacological induction (menadione, SN-38, meclizine), antioxidant rescue experiments, gene expression assays, senescence-associated β-galactosidase staining, siRNA knockdown of c-MYC\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function and pharmacological rescue with defined cellular phenotypes, single lab\",\n      \"pmids\": [\"23364789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PRC (PPRC1) and c-MYC act in concert through Akt-GSK-3 signaling to reprogram gene expression in response to mitochondrial stress. GSK-3 phosphorylation of two serine residues in the PRC C-terminal domain reduces PRC steady-state expression; mutation of these GSK-3 sites markedly increased PRC protein levels. CCCP-induced mitochondrial uncoupling activated Akt, which phospho-inactivated GSK-3β, thereby stabilizing PRC post-translationally. c-MYC inhibition blocked PRC induction, and Akt inhibition blocked both c-MYC and PRC induction.\",\n      \"method\": \"GSK-3 site mutagenesis, pharmacological inhibitors (10058-F4, AZD2858, MK-2206), c-MYC siRNA silencing, protein half-life measurements, Akt inhibitor experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of phosphorylation sites combined with pharmacological epistasis and siRNA, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"27789709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PDE5 inhibition by sildenafil induces PRC (PPRC1) expression through a cAMP- and CREB-dependent mechanism, independently of Akt3. PRC induction by sildenafil rescued mitochondrial dysfunction (uncoupled oxygen consumption, mitochondrial DNA content, VDAC expression) caused by Akt3 depletion and promoted angiogenesis, demonstrating that PRC can functionally substitute for PGC-1α during mitochondrial stress.\",\n      \"method\": \"Akt3 siRNA depletion, sildenafil treatment, oxygen consumption assays, mitochondrial DNA quantification, VDAC protein expression, tube formation angiogenesis assays, cAMP pathway analysis, CREB reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetic and pharmacological) with functional readouts, single lab\",\n      \"pmids\": [\"33087445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PRC (PPRC1) overexpression in HUVECs suppresses LPS-induced endothelial inflammation by inhibiting NF-κB transcriptional activity, reducing VCAM-1 and E-selectin expression, attenuating monocyte adhesion, and protecting mitochondrial metabolic function.\",\n      \"method\": \"Overexpression in HUVECs, NF-κB reporter assay, VCAM-1/E-selectin expression assays, monocyte adhesion assay, mitochondrial function measurement\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — overexpression with multiple functional readouts but single lab, no endogenous loss-of-function\",\n      \"pmids\": [\"23954632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PRC (PPRC1) cooperates with STAT6 to induce M2 microglia polarization; PRC overexpression increased arginase-1 (Arg1), Fizz1 (Retnla), and Ym1 (Chi3l3) expression, while PRC silencing attenuated M2 polarization markers.\",\n      \"method\": \"PRC overexpression and siRNA silencing in microglia, qPCR for M2 marker genes, co-immunoprecipitation or co-activation assay with STAT6\",\n      \"journal\": \"Journal of molecular neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, limited mechanistic detail on STAT6 interaction, no biochemical confirmation of direct interaction\",\n      \"pmids\": [\"24838382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Heterozygous Pprc1 knockout male mice fed a high-fat diet were resistant to diet-induced obesity with decreased adipose tissue due to elevated energy expenditure. In skeletal muscle of Pprc1+/- mice, Pprc1 showed haplo-insufficiency with down-regulation of Pgc1b and Pgc1a, while adipose tissue showed compensatory upregulation of other PGC-1 family members and respiratory chain genes, establishing Pprc1's role in controlling mitochondrial gene expression and energy metabolic processes in vivo.\",\n      \"method\": \"Heterozygous knockout mouse model, high-fat diet challenge, metabolic phenotyping (energy expenditure, adipose tissue mass), qPCR for mitochondrial and PGC-1 family genes\",\n      \"journal\": \"Endocrine journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model with multiple metabolic readouts, single lab\",\n      \"pmids\": [\"25994039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PPRC1 expression levels directly correlate with expression of mitochondrial proteins TFAM and SDHA in human dermal fibroblasts across multiple cell lines, whereas PGC-1α expression does not, suggesting PPRC1 is a functionally active regulator of mitochondrial biogenesis in fibroblasts. PGC-1α knockdown led to a slight decrease in TFAM protein and mtDNA-encoded MT-CO2, supporting cooperative roles for PGC-1α and PPRC1.\",\n      \"method\": \"Gene expression correlation across 10 cell lines, siRNA knockdown of PGC-1α, protein expression analysis (TFAM, SDHA, MT-CO2)\",\n      \"journal\": \"Genetics and molecular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — correlative expression analysis with limited mechanistic knockdown of PPRC1 itself\",\n      \"pmids\": [\"32639509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"COL5A1 overexpression in glioblastoma upregulates PPRC1 and downstream ESM1, promoting cell mobility, metastatic ability, and actin polymerization, placing PPRC1 as an intermediate transcription factor in the COL5A1-PPRC1-ESM1 signaling axis in GBM.\",\n      \"method\": \"Transcriptomics dataset from COL5A1 overexpression, IPA pathway analysis, functional validation of cell mobility and actin polymerization\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3-4 — pathway placement based on transcriptomics and IPA prediction with limited direct mechanistic validation of PPRC1's role\",\n      \"pmids\": [\"34702798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Eugenol inhibits AML cell growth and promotes apoptosis through the mitochondrial pathway by downregulating PPRC1 at both protein and mRNA levels and reducing mitochondrial membrane potential, establishing PPRC1 as a pro-survival regulator of mitochondrial biogenesis in AML cells.\",\n      \"method\": \"Eugenol treatment of AML cell lines and primary patient cells, apoptosis assays, qPCR and western blot for PPRC1, mitochondrial membrane potential measurement, cytarabine-resistant cell testing\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pharmacological target engagement with multiple cell models and orthogonal readouts, but no direct PPRC1 loss-of-function rescue\",\n      \"pmids\": [\"39996733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A novel heterozygous point mutation in PPRC1 (c.2902C>T, p.Thr958Ile) segregated with premature ovarian failure in a Chinese family. In vitro expression of PPRC1 in COV434 granulosa cells suggested PPRC1 is involved in regulating granulosa cell apoptosis but not senescence.\",\n      \"method\": \"Whole exome sequencing, Sanger sequencing, pedigree analysis, PPRC1 overexpression in granulosa cells, apoptosis assay, senescence staining\",\n      \"journal\": \"The journal of gene medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single family pedigree, limited in vitro mechanistic follow-up\",\n      \"pmids\": [\"33818872\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPRC1 (PRC/PGC-1-related coactivator) is a growth-regulated transcriptional coactivator that is essential for mitochondrial respiratory chain gene expression and biogenesis; it is post-translationally stabilized through an Akt-GSK-3 signaling axis in response to mitochondrial stress, acts in concert with c-MYC to reprogram gene expression during cellular stress (apoptosis, senescence, metabolic challenge), and suppresses NF-κB-driven endothelial inflammation, with in vivo evidence from heterozygous knockout mice confirming its role in energy expenditure and metabolic regulation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PPRC1 is a growth-regulated transcriptional coactivator that functions as a critical regulator of mitochondrial biogenesis, respiratory chain gene expression, and cellular stress responses. Knockdown of PPRC1 severely impairs respiratory chain function, reduces expression of complexes I–IV, diminishes mitochondrial ATP production, and causes proliferation of abnormal mitochondria lacking organized cristae [PMID:19036724]. PPRC1 protein stability is controlled post-translationally through an Akt–GSK-3β signaling axis: GSK-3 phosphorylation of C-terminal serine residues promotes PPRC1 degradation, while mitochondrial stress activates Akt to phospho-inactivate GSK-3β and stabilize PPRC1, acting in concert with c-MYC to reprogram gene expression during apoptosis and premature senescence [PMID:27789709, PMID:23364789]. In vivo, heterozygous Pprc1 knockout mice exhibit elevated energy expenditure and resistance to diet-induced obesity, with haploinsufficiency causing downregulation of PGC-1α and PGC-1β in skeletal muscle, confirming a non-redundant role in systemic energy metabolism [PMID:25994039].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"The foundational question of whether PPRC1 is required for mitochondrial function was resolved: PPRC1 loss of function causes comprehensive respiratory chain failure and mitochondrial structural disorganization, establishing it as an essential regulator of mitochondrial biogenesis.\",\n      \"evidence\": \"Lentiviral shRNA knockdown with two independent hairpins in U2OS cells, measuring respiratory enzyme activity, ATP production, gene expression by microarray, and mitochondrial ultrastructure by electron microscopy\",\n      \"pmids\": [\"19036724\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No identification of specific transcription factor partners through which PPRC1 drives respiratory gene expression\",\n        \"In vivo requirement not yet tested\",\n        \"Mechanism of PPRC1 regulation itself unknown\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"PPRC1 was shown to be a stress-responsive gene activated during apoptosis and premature senescence through ROS-dependent signaling, revealing that its function extends beyond basal mitochondrial maintenance to cellular stress adaptation, with c-MYC coordinately induced alongside PPRC1.\",\n      \"evidence\": \"Pharmacological stress induction (menadione, SN-38, meclizine) with antioxidant rescue (NAC) and c-MYC siRNA in U2OS cells\",\n      \"pmids\": [\"23364789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct transcriptional mechanism linking ROS to PPRC1 promoter activation not defined\",\n        \"Whether c-MYC directly binds the PPRC1 promoter or acts indirectly not established\",\n        \"Single laboratory findings\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"PPRC1 was identified as a suppressor of NF-κB-mediated endothelial inflammation, broadening its functional scope beyond mitochondrial biogenesis to inflammatory signaling.\",\n      \"evidence\": \"PPRC1 overexpression in HUVECs with LPS stimulation, NF-κB reporter assays, VCAM-1/E-selectin expression, and monocyte adhesion assays\",\n      \"pmids\": [\"23954632\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No endogenous loss-of-function experiment to confirm anti-inflammatory role\",\n        \"Mechanism by which PPRC1 inhibits NF-κB activity not defined\",\n        \"Limited to overexpression system in a single lab\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"In vivo genetic evidence confirmed PPRC1's non-redundant role in energy metabolism: heterozygous knockout mice showed elevated energy expenditure and resistance to diet-induced obesity, with tissue-specific haploinsufficiency effects on PGC-1 family members.\",\n      \"evidence\": \"Pprc1 heterozygous knockout mice on high-fat diet with metabolic phenotyping and gene expression profiling in skeletal muscle and adipose tissue\",\n      \"pmids\": [\"25994039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Complete knockout phenotype not reported (likely embryonic lethal but not characterized)\",\n        \"Tissue-specific conditional knockout not performed\",\n        \"Mechanism of compensatory PGC-1 family upregulation in adipose tissue unknown\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The post-translational regulation of PPRC1 was elucidated: GSK-3 phosphorylates two C-terminal serine residues to destabilize PPRC1, while mitochondrial stress activates the Akt–GSK-3β axis to stabilize PPRC1 protein, with c-MYC acting upstream in this pathway.\",\n      \"evidence\": \"GSK-3 site mutagenesis, pharmacological epistasis with Akt (MK-2206) and GSK-3 (AZD2858) inhibitors, c-MYC siRNA, and protein half-life measurements after CCCP-induced mitochondrial uncoupling\",\n      \"pmids\": [\"27789709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The E3 ubiquitin ligase mediating GSK-3-dependent PPRC1 degradation not identified\",\n        \"Whether additional kinases regulate PPRC1 stability is unknown\",\n        \"Structural basis for GSK-3 recognition of PPRC1 not determined\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"An alternative pathway for PPRC1 induction was identified through PDE5 inhibition: sildenafil induces PPRC1 via cAMP–CREB signaling, independently of Akt3, and PPRC1 can functionally rescue mitochondrial defects caused by Akt3 depletion.\",\n      \"evidence\": \"Sildenafil treatment of Akt3-depleted endothelial cells with oxygen consumption, mtDNA, and VDAC assays; CREB reporter and cAMP pathway analysis\",\n      \"pmids\": [\"33087445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct CREB binding to PPRC1 promoter not demonstrated by ChIP\",\n        \"Whether PPRC1 fully substitutes for PGC-1α in vivo not tested\",\n        \"Single laboratory\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A heterozygous missense mutation in PPRC1 (p.Thr958Ile) was linked to familial premature ovarian failure, suggesting a role for PPRC1 in ovarian granulosa cell survival.\",\n      \"evidence\": \"Whole exome sequencing and Sanger validation in a single Chinese family; PPRC1 overexpression in COV434 granulosa cells with apoptosis assays\",\n      \"pmids\": [\"33818872\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single family pedigree without replication in independent cohorts\",\n        \"No demonstration that the Thr958Ile variant causes loss of function biochemically\",\n        \"Granulosa cell phenotype based on overexpression, not endogenous mutation modeling\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Pharmacological downregulation of PPRC1 by eugenol in AML cells induced mitochondrial depolarization and apoptosis, supporting PPRC1 as a pro-survival factor that maintains mitochondrial integrity in leukemia.\",\n      \"evidence\": \"Eugenol treatment of AML cell lines and primary patient cells with PPRC1 mRNA/protein quantification, mitochondrial membrane potential assays, and apoptosis measurement\",\n      \"pmids\": [\"39996733\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct PPRC1 loss-of-function rescue to confirm PPRC1 as the critical eugenol target\",\n        \"Whether PPRC1 dependence is specific to AML or general across cancers is unknown\",\n        \"Eugenol has pleiotropic effects; PPRC1 may be a secondary target\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the E3 ligase mediating GSK-3-dependent PPRC1 degradation, the direct transcription factor partners through which PPRC1 activates respiratory chain gene promoters, and whether complete PPRC1 loss is embryonic lethal.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural information for PPRC1 or its coactivator domains\",\n        \"Genome-wide direct target identification by ChIP-seq not performed\",\n        \"Conditional tissue-specific knockout models lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"MYC\",\n      \"GSK3B\",\n      \"AKT1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}