{"gene":"PPRC1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2008,"finding":"Stable shRNA-mediated knockdown of PRC (PPRC1) in U2OS cells caused severe inhibition of respiratory growth, reduced expression of respiratory protein subunits from complexes I, II, III, and IV, markedly lower complex I and IV enzyme activities, diminished mitochondrial ATP production, and a striking proliferation of abnormal mitochondria devoid of organized cristae. Both complete and partial knockdown lines showed reduced growth on glucose and inhibition of G1/S cell cycle progression, establishing PRC as required for mitochondrial respiratory function and cell cycle progression.","method":"Lentiviral shRNA knockdown (two independent shRNAs), respiratory enzyme assays, mitochondrial morphology (electron microscopy), ATP production assay, microarray gene expression, cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent shRNA lines with consistent phenotypes, multiple orthogonal functional readouts (enzyme activity, ATP, morphology, cell cycle), single lab but rigorous controls","pmids":["19036724"],"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. PRC protein stability is negatively regulated by GSK-3 phosphorylation at two serine residues in its carboxyl-terminal domain; mutation of these sites markedly increased PRC steady-state expression. CCCP-induced mitochondrial uncoupling activated Akt, which phosphorylated and inactivated GSK-3β, thereby increasing PRC protein half-life. The Akt inhibitor MK-2206 blocked CCCP-induced induction of PRC, c-MYC, and PRC-dependent stress genes. c-MYC siRNA silencing and a c-MYC inhibitor each suppressed PRC induction, demonstrating a requirement for c-MYC in the stress program.","method":"GSK-3 phosphorylation site mutagenesis, c-MYC siRNA silencing, pharmacological inhibitors (MK-2206 Akt inhibitor, 10058-F4 c-MYC inhibitor, AZD2858 GSK-3 inhibitor, CCCP), protein half-life measurement, reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — active-site/phosphosite mutagenesis plus multiple pharmacological and siRNA approaches in a single study, single lab","pmids":["27789709"],"is_preprint":false},{"year":2013,"finding":"PRC (PPRC1) orchestrates a stress-response inflammatory program that is activated during apoptosis and premature senescence. PRC and its target genes (IL1α, SPRR2D, SPRR2F) were rapidly induced by menadione (apoptosis inducer via intracellular ROS) and this induction was blocked by the antioxidant N-acetylcysteine, placing PRC downstream of intracellular oxidants. The topoisomerase I inhibitor SN-38 also activated the PRC program over an extended, antioxidant-insensitive time course coincident with senescence markers. Meclizine (promotes glycolytic metabolism) potently induced PRC and increased lactate production. c-MYC and PRC were coordinately induced under all conditions tested.","method":"Pharmacological induction/inhibition (menadione, SN-38, meclizine, N-acetylcysteine), immunoblotting, senescence-associated β-galactosidase assay, lactate production assay, gene expression analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple inducers and inhibitors with consistent results, single lab, no direct mutagenesis or structural data","pmids":["23364789"],"is_preprint":false},{"year":2020,"finding":"Sildenafil (PDE5 inhibitor) induces PRC (PPRC1) expression through a cAMP/CREB-dependent mechanism independently of Akt3. PRC induction by sildenafil rescued mitochondrial homeostasis defects (decreased uncoupled oxygen consumption, increased fission, decreased membrane potential) caused by Akt3 depletion in primary endothelial cells, and promoted angiogenesis. PRC was shown to functionally substitute for absent PGC-1α activity during mitochondrial stress via this Akt3-independent pathway.","method":"Akt3 siRNA depletion, pharmacological inhibition (sildenafil, Akt3 inhibitor, paraquat), oxygen consumption measurement, mitochondrial DNA content, VDAC protein expression, CREB pathway inhibition, angiogenesis assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (oxygen consumption, mtDNA, protein expression, functional rescue), single lab","pmids":["33087445"],"is_preprint":false},{"year":2013,"finding":"Overexpression of PRC (PPRC1) in human umbilical vein endothelial cells attenuated LPS-induced monocyte adhesion, decreased VCAM-1 and E-selectin expression, protected mitochondrial metabolic function, suppressed glycolysis, and decreased NF-κB transcriptional activity. LPS inhibited endogenous PRC expression, and PRC overexpression reversed these LPS-induced pro-inflammatory effects.","method":"PRC overexpression in HUVECs, monocyte adhesion assay, VCAM-1/E-selectin immunoblotting, NF-κB reporter assay, mitochondrial metabolic assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain-of-function overexpression with multiple functional readouts, single lab, no loss-of-function or structural data","pmids":["23954632"],"is_preprint":false},{"year":2014,"finding":"PRC (PPRC1) expression was induced in M2-polarized microglia. Overexpression of PRC promoted M2 polarization (increased Arg1, Fizz1, Ym1 expression), while PRC silencing attenuated M2 polarization. Mechanistically, PRC was found to cooperate with the transcription factor STAT6 to induce the M2 gene program.","method":"PRC overexpression and siRNA silencing in microglia, qRT-PCR for M2 marker genes, co-immunoprecipitation/co-operation assay with STAT6","journal":"Journal of molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — bidirectional manipulation (OE and KD) with consistent phenotypes, single lab, STAT6 interaction assay","pmids":["24838382"],"is_preprint":false},{"year":2015,"finding":"Male Pprc1 heterozygous knockout mice on a high-fat diet showed resistance to diet-induced obesity with decreased adipose tissue and elevated energy expenditure. In skeletal muscle, Pprc1 showed haploinsufficiency with down-regulation of Pgc1b and Pgc1a. In adipose tissue, compensatory increases in other Pgc1 family members drove up-regulation of respiratory chain genes. These results established an in vivo role for Pprc1 in controlling mitochondrial gene expression and energy metabolic processes.","method":"Heterozygous Pprc1 knockout mouse model, high-fat diet challenge, metabolic phenotyping (energy expenditure, adipose tissue mass), gene expression analysis of PGC family members and respiratory chain genes","journal":"Endocrine journal","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo genetic loss-of-function with defined metabolic phenotype, but single lab and partial mechanistic follow-up (whole-body KO lethal, only het available)","pmids":["25994039"],"is_preprint":false},{"year":2020,"finding":"In human dermal fibroblasts, PPRC1 expression level directly correlated with the expression of mitochondrial proteins TFAM and SDHA across 10 cell lines, whereas PGC-1α expression did not show this correlation. This establishes PPRC1 as more tightly linked than PGC-1α to mitochondrial biogenesis maintenance in fibroblasts.","method":"Correlation analysis of PPRC1 and PGC-1α mRNA with TFAM and SDHA protein levels across multiple cell lines; PGC-1α knockdown with TFAM/MT-CO2 protein measurement","journal":"Genetics and molecular biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlational approach in cell lines with limited mechanistic follow-up, single lab","pmids":["32639509"],"is_preprint":false},{"year":2021,"finding":"In a GBM cell model, COL5A1 overexpression activated PPRC1 expression, and PPRC1 was predicted by pathway analysis to act downstream of COL5A1 and upstream of ESM1, forming a COL5A1-PPRC1-ESM1 axis associated with cell mobility, metastatic ability, and actin polymerization status. PPRC1 was identified as a transcription factor or downstream participant in this pathway.","method":"Transcriptomics dataset from COL5A1-overexpressing cells, ingenuity pathway analysis (IPA), cell mobility and actin polymerization assays","journal":"Cell death discovery","confidence":"Low","confidence_rationale":"Tier 4 / Weak — primarily computational/transcriptomic pathway inference with limited direct mechanistic validation of PPRC1's role","pmids":["34702798"],"is_preprint":false},{"year":2025,"finding":"Eugenol downregulated PPRC1 at both protein and mRNA levels in AML cell lines and reduced mitochondrial membrane potential, promoting apoptosis through the mitochondrial pathway. PPRC1 expression was higher in cancer cells than normal cells, and PPRC1 overexpression was shown to be relevant to AML cell survival, implicating PPRC1 as a regulator of mitochondrial biogenesis required for AML cell survival.","method":"Eugenol treatment of AML cell lines and primary AML cells, immunoblotting, qRT-PCR, mitochondrial membrane potential assay, apoptosis assay (mitochondrial pathway markers)","journal":"Cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological downregulation of PPRC1 with phenotypic readout, single lab, indirect mechanism (drug effect, not direct PPRC1 manipulation)","pmids":["39996733"],"is_preprint":false},{"year":2021,"finding":"A novel point mutation in PPRC1 (c.2902C>T; p.Thr958Ile) was identified in a Chinese family with premature ovarian failure (POF). Overexpression of PPRC1 in COV434 granulosa cells suggested PPRC1 may be involved in regulating granulosa cell apoptosis but not senescence-associated POF development.","method":"Whole exome sequencing, Sanger sequencing, PPRC1 overexpression in COV434 granulosa cells, apoptosis assay, senescence staining","journal":"The journal of gene medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single family genetic study with partial in vitro functional follow-up, single lab, limited mechanistic depth","pmids":["33818872"],"is_preprint":false}],"current_model":"PPRC1 (PRC) is a growth-regulated transcriptional coactivator of the PGC-1 family that is required for mitochondrial respiratory chain gene expression and normal mitochondrial biogenesis; its protein stability is post-translationally controlled by GSK-3-mediated phosphorylation downstream of Akt signaling, and it cooperates with c-MYC through the Akt-GSK-3 axis to orchestrate an inflammatory/metabolic stress-response program activated by ROS, mitochondrial dysfunction, and genotoxic stress, while also suppressing NF-κB-dependent endothelial inflammation and cooperating with STAT6 to promote microglial M2 polarization."},"narrative":{"mechanistic_narrative":"PPRC1 (PRC) is a growth-regulated transcriptional coactivator required for mitochondrial respiratory chain gene expression and normal mitochondrial biogenesis [PMID:19036724]. Its depletion in human cells reduces expression of complex I–IV subunits, lowers complex I and IV enzyme activities and mitochondrial ATP production, produces structurally abnormal mitochondria lacking organized cristae, and impairs glucose-supported growth and G1/S progression, establishing PPRC1 as essential for both respiratory function and cell cycle progression [PMID:19036724]. PPRC1 protein stability is post-translationally controlled by GSK-3-mediated phosphorylation at two C-terminal serines; mitochondrial uncoupling activates Akt, which inactivates GSK-3β and extends PPRC1 half-life, and PPRC1 acts in concert with c-MYC through this Akt-GSK-3 axis to reprogram gene expression under mitochondrial stress [PMID:27789709]. The PPRC1 program is induced downstream of intracellular ROS and during apoptosis and premature senescence, driving target genes such as IL1α and the SPRR2 family, and PPRC1 can also be induced through a cAMP/CREB-dependent route that substitutes for absent PGC-1α activity to restore mitochondrial homeostasis [PMID:23364789, PMID:33087445]. Beyond its core biogenesis role, PPRC1 suppresses NF-κB-dependent endothelial inflammation [PMID:23954632] and cooperates with STAT6 to promote microglial M2 polarization [PMID:24838382]. In vivo, Pprc1 haploinsufficiency in mice perturbs PGC-family and respiratory-chain gene expression and confers resistance to diet-induced obesity with elevated energy expenditure [PMID:25994039]. A point mutation in PPRC1 (p.Thr958Ile) was identified in a family with premature ovarian failure [PMID:33818872].","teleology":[{"year":2008,"claim":"Established that PPRC1 is functionally required for mitochondrial respiratory function rather than merely correlated with it, resolving whether the PGC-1 family member PRC has a non-redundant biogenesis role.","evidence":"Stable lentiviral shRNA knockdown in U2OS cells with respiratory enzyme assays, EM mitochondrial morphology, ATP and cell cycle readouts","pmids":["19036724"],"confidence":"High","gaps":["Does not identify direct transcription-factor partners through which PPRC1 activates respiratory genes","Mechanism linking respiratory defect to G1/S arrest not defined"]},{"year":2013,"claim":"Defined the upstream signals that activate the PPRC1 program, placing it downstream of intracellular ROS and linking it to apoptosis, senescence, and glycolytic metabolic shifts.","evidence":"Pharmacological induction/inhibition (menadione, SN-38, meclizine, N-acetylcysteine) with immunoblotting, SA-β-gal and lactate assays","pmids":["23364789"],"confidence":"Medium","gaps":["No direct mutagenesis or structural mapping of the stress-responsive elements","Coordinate c-MYC/PRC induction observed but causal hierarchy not yet established in this study"]},{"year":2013,"claim":"Showed PPRC1 acts as an anti-inflammatory regulator in endothelium, connecting its mitochondrial/metabolic role to suppression of NF-κB signaling.","evidence":"PPRC1 overexpression in HUVECs with monocyte adhesion, VCAM-1/E-selectin immunoblotting, NF-κB reporter and metabolic assays","pmids":["23954632"],"confidence":"Medium","gaps":["Gain-of-function only; no loss-of-function confirmation","Direct molecular link between PPRC1 and NF-κB not defined"]},{"year":2014,"claim":"Extended PPRC1 function into immune cell programming by showing it cooperates with STAT6 to drive microglial M2 polarization.","evidence":"PPRC1 overexpression and siRNA silencing in microglia, qRT-PCR of M2 markers, STAT6 co-operation/co-IP assay","pmids":["24838382"],"confidence":"Medium","gaps":["Direct PPRC1-STAT6 binding interface not mapped","Reciprocal validation of the interaction limited"]},{"year":2015,"claim":"Provided in vivo genetic evidence that Pprc1 controls mitochondrial gene expression and whole-body energy metabolism.","evidence":"Heterozygous Pprc1 knockout mice on high-fat diet, metabolic phenotyping and PGC-family/respiratory gene expression analysis","pmids":["25994039"],"confidence":"Medium","gaps":["Whole-body knockout lethal, so only heterozygotes assessed","Tissue-specific mechanisms (muscle haploinsufficiency vs adipose compensation) not fully resolved"]},{"year":2016,"claim":"Defined the post-translational control of PPRC1, showing GSK-3 phosphorylation destabilizes the protein and Akt-mediated GSK-3 inactivation stabilizes it, with c-MYC required for the stress program.","evidence":"GSK-3 phosphosite mutagenesis, c-MYC siRNA and inhibitor, Akt/GSK-3 inhibitors, CCCP, protein half-life and reporter assays","pmids":["27789709"],"confidence":"High","gaps":["Identity of the kinase priming GSK-3 phosphorylation not established","How c-MYC and PPRC1 jointly engage target promoters not resolved"]},{"year":2020,"claim":"Showed PPRC1 can be induced through an Akt-independent cAMP/CREB route and can functionally substitute for PGC-1α to rescue mitochondrial homeostasis.","evidence":"Akt3 siRNA depletion, sildenafil and CREB pathway inhibition in primary endothelial cells, oxygen consumption, mtDNA, VDAC and angiogenesis assays","pmids":["33087445"],"confidence":"Medium","gaps":["Direct CREB binding to the PPRC1 locus not demonstrated","Mechanism of PGC-1α functional substitution not detailed"]},{"year":2020,"claim":"Correlated PPRC1 expression with mitochondrial protein levels more tightly than PGC-1α, positioning PPRC1 as a primary maintainer of mitochondrial biogenesis in fibroblasts.","evidence":"Correlation of PPRC1/PGC-1α mRNA with TFAM and SDHA protein across cell lines, plus PGC-1α knockdown","pmids":["32639509"],"confidence":"Low","gaps":["Correlational design without direct PPRC1 manipulation","Causality between PPRC1 and TFAM/SDHA not established"]},{"year":2021,"claim":"Implicated PPRC1 in a cancer-associated migration/metastasis pathway as part of a predicted COL5A1-PPRC1-ESM1 axis.","evidence":"Transcriptomics of COL5A1-overexpressing GBM cells, ingenuity pathway analysis, cell mobility and actin polymerization assays","pmids":["34702798"],"confidence":"Low","gaps":["Largely computational pathway inference","Direct PPRC1 manipulation in the migration phenotype not performed"]},{"year":2021,"claim":"Linked PPRC1 to a human disease by identifying a point mutation in a family with premature ovarian failure and a possible role in granulosa cell apoptosis.","evidence":"Whole exome and Sanger sequencing of a Chinese POF family, PPRC1 overexpression in COV434 granulosa cells, apoptosis and senescence assays","pmids":["33818872"],"confidence":"Low","gaps":["Single family without functional validation of the mutation's pathogenicity","Mechanism connecting PPRC1 to granulosa cell apoptosis unresolved"]},{"year":2025,"claim":"Implicated PPRC1 in AML cell survival via its mitochondrial biogenesis role, with pharmacological downregulation promoting mitochondrial apoptosis.","evidence":"Eugenol treatment of AML cell lines/primary cells, immunoblotting, qRT-PCR, membrane potential and apoptosis assays","pmids":["39996733"],"confidence":"Low","gaps":["Effect inferred from drug treatment rather than direct PPRC1 perturbation","Mechanism of selective dependence in AML not defined"]},{"year":null,"claim":"The direct DNA-binding transcription factors and coactivation complexes through which PPRC1 activates respiratory and stress-response gene programs remain unidentified.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of PPRC1 or its activation domains","Genome-wide PPRC1 occupancy and direct target promoters not mapped","Priming kinase upstream of GSK-3 phosphorylation unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3]}],"complexes":[],"partners":["MYC","STAT6","GSK3B"],"other_free_text":[]}},"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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aeruginosa.","date":"2024","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/39287400","citation_count":2,"is_preprint":false},{"pmid":"34975778","id":"PMC_34975778","title":"Characterization of a Novel Chromosome-Encoded AmpC β-Lactamase Gene, bla PRC-1, in an Isolate of a Newly Classified Pseudomonas Species, 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":"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":1,"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 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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":"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 plant-microbe interactions : MPMI","url":"https://pubmed.ncbi.nlm.nih.gov/30958087","citation_count":1,"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":1,"is_preprint":false},{"pmid":"38338887","id":"PMC_38338887","title":"Significantly Improved Cold Preservation of Rat Hind Limb Vascularized Composite Allografts Using the New PrC-210 Free Radical Scavenger.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38338887","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":"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":"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":"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_2025.02.10.637455","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_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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43115,"output_tokens":3883,"usd":0.093795,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11021,"output_tokens":3748,"usd":0.074402,"stage2_stop_reason":"end_turn"},"total_usd":0.168197,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"I need to carefully distinguish papers about PPRC1 (PGC-1-related coactivator, also known as PRC in the mammalian coactivator sense) from papers about bacterial Prc proteases, progesterone receptor isoforms, PRC complexes (Polycomb), and other unrelated uses of \"PRC.\"\n\nPPRC1 (HGNC: PPRC1, aliases PRC, KIAA0595, MGC74642) is the human gene encoding PGC-1-related coactivator — a transcriptional coactivator in the PGC-1 family involved in mitochondrial biogenesis and metabolic regulation.\n\nPapers about PPRC1/PRC (mammalian coactivator):\n- PMID:19036724 (shRNA silencing of PRC in U2OS cells)\n- PMID:27789709 (PRC and c-MYC stress response)\n- PMID:23364789 (PRC stress program, apoptosis/senescence)\n- PMID:33087445 (PDE5 inhibition, PRC expression, Akt3)\n- PMID:23954632 (PRC inhibits NF-κB, endothelial inflammation)\n- PMID:24838382 (PRC in microglia M2 polarization)\n- PMID:25994039 (Pprc1 heterozygous KO mice, metabolism)\n- PMID:32639509 (PPRC1 correlates with mitochondrial proteins)\n- PMID:34702798 (COL5A1-PPRC1-ESM1 axis in GBM)\n- PMID:33818872 (PPRC1 mutation and premature ovarian failure)\n- PMID:39996733 (eugenol targets PPRC1 in AML)\n\nAll bacterial Prc protease papers, progesterone receptor PR-C papers, Polycomb PRC1/PRC2 papers, PrC-210 aminothiol papers, and other unrelated papers are excluded.\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 growth, reduced expression of respiratory protein subunits from complexes I, II, III, and IV, markedly lower complex I and IV enzyme activities, diminished mitochondrial ATP production, and a striking proliferation of abnormal mitochondria devoid of organized cristae. Both complete and partial knockdown lines showed reduced growth on glucose and inhibition of G1/S cell cycle progression, establishing PRC as required for mitochondrial respiratory function and cell cycle progression.\",\n      \"method\": \"Lentiviral shRNA knockdown (two independent shRNAs), respiratory enzyme assays, mitochondrial morphology (electron microscopy), ATP production assay, microarray gene expression, cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent shRNA lines with consistent phenotypes, multiple orthogonal functional readouts (enzyme activity, ATP, morphology, cell cycle), single lab but rigorous controls\",\n      \"pmids\": [\"19036724\"],\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. PRC protein stability is negatively regulated by GSK-3 phosphorylation at two serine residues in its carboxyl-terminal domain; mutation of these sites markedly increased PRC steady-state expression. CCCP-induced mitochondrial uncoupling activated Akt, which phosphorylated and inactivated GSK-3β, thereby increasing PRC protein half-life. The Akt inhibitor MK-2206 blocked CCCP-induced induction of PRC, c-MYC, and PRC-dependent stress genes. c-MYC siRNA silencing and a c-MYC inhibitor each suppressed PRC induction, demonstrating a requirement for c-MYC in the stress program.\",\n      \"method\": \"GSK-3 phosphorylation site mutagenesis, c-MYC siRNA silencing, pharmacological inhibitors (MK-2206 Akt inhibitor, 10058-F4 c-MYC inhibitor, AZD2858 GSK-3 inhibitor, CCCP), protein half-life measurement, reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — active-site/phosphosite mutagenesis plus multiple pharmacological and siRNA approaches in a single study, single lab\",\n      \"pmids\": [\"27789709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PRC (PPRC1) orchestrates a stress-response inflammatory program that is activated during apoptosis and premature senescence. PRC and its target genes (IL1α, SPRR2D, SPRR2F) were rapidly induced by menadione (apoptosis inducer via intracellular ROS) and this induction was blocked by the antioxidant N-acetylcysteine, placing PRC downstream of intracellular oxidants. The topoisomerase I inhibitor SN-38 also activated the PRC program over an extended, antioxidant-insensitive time course coincident with senescence markers. Meclizine (promotes glycolytic metabolism) potently induced PRC and increased lactate production. c-MYC and PRC were coordinately induced under all conditions tested.\",\n      \"method\": \"Pharmacological induction/inhibition (menadione, SN-38, meclizine, N-acetylcysteine), immunoblotting, senescence-associated β-galactosidase assay, lactate production assay, gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple inducers and inhibitors with consistent results, single lab, no direct mutagenesis or structural data\",\n      \"pmids\": [\"23364789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Sildenafil (PDE5 inhibitor) induces PRC (PPRC1) expression through a cAMP/CREB-dependent mechanism independently of Akt3. PRC induction by sildenafil rescued mitochondrial homeostasis defects (decreased uncoupled oxygen consumption, increased fission, decreased membrane potential) caused by Akt3 depletion in primary endothelial cells, and promoted angiogenesis. PRC was shown to functionally substitute for absent PGC-1α activity during mitochondrial stress via this Akt3-independent pathway.\",\n      \"method\": \"Akt3 siRNA depletion, pharmacological inhibition (sildenafil, Akt3 inhibitor, paraquat), oxygen consumption measurement, mitochondrial DNA content, VDAC protein expression, CREB pathway inhibition, angiogenesis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (oxygen consumption, mtDNA, protein expression, functional rescue), single lab\",\n      \"pmids\": [\"33087445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Overexpression of PRC (PPRC1) in human umbilical vein endothelial cells attenuated LPS-induced monocyte adhesion, decreased VCAM-1 and E-selectin expression, protected mitochondrial metabolic function, suppressed glycolysis, and decreased NF-κB transcriptional activity. LPS inhibited endogenous PRC expression, and PRC overexpression reversed these LPS-induced pro-inflammatory effects.\",\n      \"method\": \"PRC overexpression in HUVECs, monocyte adhesion assay, VCAM-1/E-selectin immunoblotting, NF-κB reporter assay, mitochondrial metabolic assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain-of-function overexpression with multiple functional readouts, single lab, no loss-of-function or structural data\",\n      \"pmids\": [\"23954632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PRC (PPRC1) expression was induced in M2-polarized microglia. Overexpression of PRC promoted M2 polarization (increased Arg1, Fizz1, Ym1 expression), while PRC silencing attenuated M2 polarization. Mechanistically, PRC was found to cooperate with the transcription factor STAT6 to induce the M2 gene program.\",\n      \"method\": \"PRC overexpression and siRNA silencing in microglia, qRT-PCR for M2 marker genes, co-immunoprecipitation/co-operation assay with STAT6\",\n      \"journal\": \"Journal of molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — bidirectional manipulation (OE and KD) with consistent phenotypes, single lab, STAT6 interaction assay\",\n      \"pmids\": [\"24838382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Male Pprc1 heterozygous knockout mice on a high-fat diet showed resistance to diet-induced obesity with decreased adipose tissue and elevated energy expenditure. In skeletal muscle, Pprc1 showed haploinsufficiency with down-regulation of Pgc1b and Pgc1a. In adipose tissue, compensatory increases in other Pgc1 family members drove up-regulation of respiratory chain genes. These results established an in vivo role for Pprc1 in controlling mitochondrial gene expression and energy metabolic processes.\",\n      \"method\": \"Heterozygous Pprc1 knockout mouse model, high-fat diet challenge, metabolic phenotyping (energy expenditure, adipose tissue mass), gene expression analysis of PGC family members and respiratory chain genes\",\n      \"journal\": \"Endocrine journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo genetic loss-of-function with defined metabolic phenotype, but single lab and partial mechanistic follow-up (whole-body KO lethal, only het available)\",\n      \"pmids\": [\"25994039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In human dermal fibroblasts, PPRC1 expression level directly correlated with the expression of mitochondrial proteins TFAM and SDHA across 10 cell lines, whereas PGC-1α expression did not show this correlation. This establishes PPRC1 as more tightly linked than PGC-1α to mitochondrial biogenesis maintenance in fibroblasts.\",\n      \"method\": \"Correlation analysis of PPRC1 and PGC-1α mRNA with TFAM and SDHA protein levels across multiple cell lines; PGC-1α knockdown with TFAM/MT-CO2 protein measurement\",\n      \"journal\": \"Genetics and molecular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlational approach in cell lines with limited mechanistic follow-up, single lab\",\n      \"pmids\": [\"32639509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In a GBM cell model, COL5A1 overexpression activated PPRC1 expression, and PPRC1 was predicted by pathway analysis to act downstream of COL5A1 and upstream of ESM1, forming a COL5A1-PPRC1-ESM1 axis associated with cell mobility, metastatic ability, and actin polymerization status. PPRC1 was identified as a transcription factor or downstream participant in this pathway.\",\n      \"method\": \"Transcriptomics dataset from COL5A1-overexpressing cells, ingenuity pathway analysis (IPA), cell mobility and actin polymerization assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — primarily computational/transcriptomic pathway inference with limited direct mechanistic validation of PPRC1's role\",\n      \"pmids\": [\"34702798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Eugenol downregulated PPRC1 at both protein and mRNA levels in AML cell lines and reduced mitochondrial membrane potential, promoting apoptosis through the mitochondrial pathway. PPRC1 expression was higher in cancer cells than normal cells, and PPRC1 overexpression was shown to be relevant to AML cell survival, implicating PPRC1 as a regulator of mitochondrial biogenesis required for AML cell survival.\",\n      \"method\": \"Eugenol treatment of AML cell lines and primary AML cells, immunoblotting, qRT-PCR, mitochondrial membrane potential assay, apoptosis assay (mitochondrial pathway markers)\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological downregulation of PPRC1 with phenotypic readout, single lab, indirect mechanism (drug effect, not direct PPRC1 manipulation)\",\n      \"pmids\": [\"39996733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A novel point mutation in PPRC1 (c.2902C>T; p.Thr958Ile) was identified in a Chinese family with premature ovarian failure (POF). Overexpression of PPRC1 in COV434 granulosa cells suggested PPRC1 may be involved in regulating granulosa cell apoptosis but not senescence-associated POF development.\",\n      \"method\": \"Whole exome sequencing, Sanger sequencing, PPRC1 overexpression in COV434 granulosa cells, apoptosis assay, senescence staining\",\n      \"journal\": \"The journal of gene medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single family genetic study with partial in vitro functional follow-up, single lab, limited mechanistic depth\",\n      \"pmids\": [\"33818872\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPRC1 (PRC) is a growth-regulated transcriptional coactivator of the PGC-1 family that is required for mitochondrial respiratory chain gene expression and normal mitochondrial biogenesis; its protein stability is post-translationally controlled by GSK-3-mediated phosphorylation downstream of Akt signaling, and it cooperates with c-MYC through the Akt-GSK-3 axis to orchestrate an inflammatory/metabolic stress-response program activated by ROS, mitochondrial dysfunction, and genotoxic stress, while also suppressing NF-κB-dependent endothelial inflammation and cooperating with STAT6 to promote microglial M2 polarization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PPRC1 (PRC) is a growth-regulated transcriptional coactivator required for mitochondrial respiratory chain gene expression and normal mitochondrial biogenesis [#0]. Its depletion in human cells reduces expression of complex I–IV subunits, lowers complex I and IV enzyme activities and mitochondrial ATP production, produces structurally abnormal mitochondria lacking organized cristae, and impairs glucose-supported growth and G1/S progression, establishing PPRC1 as essential for both respiratory function and cell cycle progression [#0]. PPRC1 protein stability is post-translationally controlled by GSK-3-mediated phosphorylation at two C-terminal serines; mitochondrial uncoupling activates Akt, which inactivates GSK-3β and extends PPRC1 half-life, and PPRC1 acts in concert with c-MYC through this Akt-GSK-3 axis to reprogram gene expression under mitochondrial stress [#1]. The PPRC1 program is induced downstream of intracellular ROS and during apoptosis and premature senescence, driving target genes such as IL1α and the SPRR2 family, and PPRC1 can also be induced through a cAMP/CREB-dependent route that substitutes for absent PGC-1α activity to restore mitochondrial homeostasis [#2, #3]. Beyond its core biogenesis role, PPRC1 suppresses NF-κB-dependent endothelial inflammation [#4] and cooperates with STAT6 to promote microglial M2 polarization [#5]. In vivo, Pprc1 haploinsufficiency in mice perturbs PGC-family and respiratory-chain gene expression and confers resistance to diet-induced obesity with elevated energy expenditure [#6]. A point mutation in PPRC1 (p.Thr958Ile) was identified in a family with premature ovarian failure [#10].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that PPRC1 is functionally required for mitochondrial respiratory function rather than merely correlated with it, resolving whether the PGC-1 family member PRC has a non-redundant biogenesis role.\",\n      \"evidence\": \"Stable lentiviral shRNA knockdown in U2OS cells with respiratory enzyme assays, EM mitochondrial morphology, ATP and cell cycle readouts\",\n      \"pmids\": [\"19036724\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify direct transcription-factor partners through which PPRC1 activates respiratory genes\", \"Mechanism linking respiratory defect to G1/S arrest not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the upstream signals that activate the PPRC1 program, placing it downstream of intracellular ROS and linking it to apoptosis, senescence, and glycolytic metabolic shifts.\",\n      \"evidence\": \"Pharmacological induction/inhibition (menadione, SN-38, meclizine, N-acetylcysteine) with immunoblotting, SA-β-gal and lactate assays\",\n      \"pmids\": [\"23364789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct mutagenesis or structural mapping of the stress-responsive elements\", \"Coordinate c-MYC/PRC induction observed but causal hierarchy not yet established in this study\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed PPRC1 acts as an anti-inflammatory regulator in endothelium, connecting its mitochondrial/metabolic role to suppression of NF-κB signaling.\",\n      \"evidence\": \"PPRC1 overexpression in HUVECs with monocyte adhesion, VCAM-1/E-selectin immunoblotting, NF-κB reporter and metabolic assays\",\n      \"pmids\": [\"23954632\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Gain-of-function only; no loss-of-function confirmation\", \"Direct molecular link between PPRC1 and NF-κB not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended PPRC1 function into immune cell programming by showing it cooperates with STAT6 to drive microglial M2 polarization.\",\n      \"evidence\": \"PPRC1 overexpression and siRNA silencing in microglia, qRT-PCR of M2 markers, STAT6 co-operation/co-IP assay\",\n      \"pmids\": [\"24838382\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PPRC1-STAT6 binding interface not mapped\", \"Reciprocal validation of the interaction limited\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided in vivo genetic evidence that Pprc1 controls mitochondrial gene expression and whole-body energy metabolism.\",\n      \"evidence\": \"Heterozygous Pprc1 knockout mice on high-fat diet, metabolic phenotyping and PGC-family/respiratory gene expression analysis\",\n      \"pmids\": [\"25994039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whole-body knockout lethal, so only heterozygotes assessed\", \"Tissue-specific mechanisms (muscle haploinsufficiency vs adipose compensation) not fully resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the post-translational control of PPRC1, showing GSK-3 phosphorylation destabilizes the protein and Akt-mediated GSK-3 inactivation stabilizes it, with c-MYC required for the stress program.\",\n      \"evidence\": \"GSK-3 phosphosite mutagenesis, c-MYC siRNA and inhibitor, Akt/GSK-3 inhibitors, CCCP, protein half-life and reporter assays\",\n      \"pmids\": [\"27789709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the kinase priming GSK-3 phosphorylation not established\", \"How c-MYC and PPRC1 jointly engage target promoters not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed PPRC1 can be induced through an Akt-independent cAMP/CREB route and can functionally substitute for PGC-1α to rescue mitochondrial homeostasis.\",\n      \"evidence\": \"Akt3 siRNA depletion, sildenafil and CREB pathway inhibition in primary endothelial cells, oxygen consumption, mtDNA, VDAC and angiogenesis assays\",\n      \"pmids\": [\"33087445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CREB binding to the PPRC1 locus not demonstrated\", \"Mechanism of PGC-1α functional substitution not detailed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Correlated PPRC1 expression with mitochondrial protein levels more tightly than PGC-1α, positioning PPRC1 as a primary maintainer of mitochondrial biogenesis in fibroblasts.\",\n      \"evidence\": \"Correlation of PPRC1/PGC-1α mRNA with TFAM and SDHA protein across cell lines, plus PGC-1α knockdown\",\n      \"pmids\": [\"32639509\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Correlational design without direct PPRC1 manipulation\", \"Causality between PPRC1 and TFAM/SDHA not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Implicated PPRC1 in a cancer-associated migration/metastasis pathway as part of a predicted COL5A1-PPRC1-ESM1 axis.\",\n      \"evidence\": \"Transcriptomics of COL5A1-overexpressing GBM cells, ingenuity pathway analysis, cell mobility and actin polymerization assays\",\n      \"pmids\": [\"34702798\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Largely computational pathway inference\", \"Direct PPRC1 manipulation in the migration phenotype not performed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked PPRC1 to a human disease by identifying a point mutation in a family with premature ovarian failure and a possible role in granulosa cell apoptosis.\",\n      \"evidence\": \"Whole exome and Sanger sequencing of a Chinese POF family, PPRC1 overexpression in COV434 granulosa cells, apoptosis and senescence assays\",\n      \"pmids\": [\"33818872\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single family without functional validation of the mutation's pathogenicity\", \"Mechanism connecting PPRC1 to granulosa cell apoptosis unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated PPRC1 in AML cell survival via its mitochondrial biogenesis role, with pharmacological downregulation promoting mitochondrial apoptosis.\",\n      \"evidence\": \"Eugenol treatment of AML cell lines/primary cells, immunoblotting, qRT-PCR, membrane potential and apoptosis assays\",\n      \"pmids\": [\"39996733\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Effect inferred from drug treatment rather than direct PPRC1 perturbation\", \"Mechanism of selective dependence in AML not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct DNA-binding transcription factors and coactivation complexes through which PPRC1 activates respiratory and stress-response gene programs remain unidentified.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of PPRC1 or its activation domains\", \"Genome-wide PPRC1 occupancy and direct target promoters not mapped\", \"Priming kinase upstream of GSK-3 phosphorylation unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MYC\", \"STAT6\", \"GSK3B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}