{"gene":"PAWR","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2015,"finding":"PAWR overexpression suppresses BCL2 and BECN1 expression, disrupts the BCL2-BECN1 interaction, and thereby switches autophagy to apoptosis in prostate cancer cells; pawr-KO MEFs exhibited abundant autophagy even at toxic concentrations of 3-AWA, establishing PAWR as essential for this switch.","method":"pawr knockout MEFs (loss-of-function), overexpression of EGFP-LC3B and DS-Red-BECN1, co-immunoprecipitation/interaction analysis of BCL2-BECN1, western blot for autophagy/apoptosis markers","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined phenotypic readout plus overexpression rescue and interaction disruption data, single lab","pmids":["25803782"],"is_preprint":false},{"year":2016,"finding":"Upregulation of PAWR by small activating RNAs (saRNAs) targeting the PAWR promoter induces apoptosis in prostate cancer cells, associated with inactivation of the NF-κB and Akt pathways, decreased BCL-2, and activation of the caspase cascade and PARP cleavage.","method":"saRNA-mediated transcriptional activation of PAWR, western blot for pathway components (NF-κB, Akt, Bcl-2, caspase, PARP), cell viability and apoptosis assays","journal":"Oncology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, gain-of-function with pathway readouts but no direct mechanistic dissection of how PAWR engages NF-κB or Akt","pmids":["26797252"],"is_preprint":false},{"year":2021,"finding":"Upregulation of PAWR by saRNAs in bladder cancer cells induces apoptosis and cell cycle arrest via inhibition of BCL-2 and inactivation of NF-κB and Akt pathways, and cooperates with cisplatin.","method":"saRNA-mediated PAWR upregulation, western blot for BCL-2, NF-κB, Akt, caspase cascade, and cell cycle proteins; cell viability and apoptosis assays","journal":"International journal of medical sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method category, pharmacological cooperation without direct mechanistic dissection","pmids":["34220332"],"is_preprint":false},{"year":2014,"finding":"The C-terminal domain of Par-4 (PAWR) was crystallized (rat homologue) and X-ray diffraction data collected to 3.7 Å resolution, revealing space group P41212, consistent with Par-4 being an intrinsically disordered protein that mediates interactions with apoptotic partners via its C-terminus.","method":"Protein expression, purification, and X-ray crystallography of the C-terminal domain","journal":"Acta crystallographica. Section F, Structural biology communications","confidence":"Low","confidence_rationale":"Tier 1 / Weak — crystallography data collected but only preliminary analysis reported (3.7 Å, no refined structure or functional validation in this report)","pmids":["25195896"],"is_preprint":false}],"current_model":"PAWR (Par-4) is a pro-apoptotic protein that promotes apoptosis by suppressing BCL2 and BECN1 expression and disrupting the BCL2-BECN1 interaction, thereby switching autophagy to apoptosis; its pro-apoptotic signaling engages the NF-κB and Akt pathways and activates the caspase cascade, while its C-terminal domain (which mediates interactions with apoptotic partners) has been structurally characterized at preliminary resolution."},"narrative":{"mechanistic_narrative":"PAWR (Par-4) is a pro-apoptotic regulator that acts as a molecular switch converting autophagy to apoptosis in cancer cells [PMID:25803782]. It suppresses BCL2 and BECN1 expression and disrupts the BCL2-BECN1 interaction; cells lacking PAWR fail to make this switch and instead accumulate abundant autophagy even under toxic stress, establishing PAWR as essential for the autophagy-to-apoptosis transition [PMID:25803782]. Beyond this switching function, the mechanistic detail of how PAWR engages downstream signaling has not been dissected in the available corpus; its C-terminal domain, which mediates interactions with apoptotic partners, is consistent with an intrinsically disordered protein but has only been characterized at preliminary crystallographic resolution [PMID:25195896].","teleology":[{"year":2014,"claim":"Addressed how Par-4 physically engages apoptotic partners by structurally characterizing its interaction-bearing region, establishing that the C-terminal domain mediates these contacts and is consistent with intrinsic disorder.","evidence":"Expression, purification, and X-ray crystallography of the rat Par-4 C-terminal domain to 3.7 Å","pmids":["25195896"],"confidence":"Low","gaps":["Only preliminary diffraction data collected; no refined structure or model deposited","No functional validation of specific partner-binding residues in this report","Human PAWR domain structure not solved"]},{"year":2015,"claim":"Resolved whether PAWR is merely correlated with cell death or causally required for switching cellular fate, showing it is essential to convert cytoprotective autophagy into apoptosis by suppressing BCL2/BECN1 and disrupting their interaction.","evidence":"pawr-knockout MEFs (loss-of-function) plus overexpression rescue, BCL2-BECN1 co-immunoprecipitation, and autophagy/apoptosis marker western blots in prostate cancer cells","pmids":["25803782"],"confidence":"Medium","gaps":["Mechanism by which PAWR suppresses BCL2/BECN1 transcription or stability not defined","Direct vs indirect disruption of the BCL2-BECN1 interface not distinguished","Single-lab finding without independent replication"]},{"year":2021,"claim":"Tested whether restoring PAWR expression is sufficient to drive apoptosis and whether this extends beyond prostate cancer, showing transcriptional upregulation induces apoptosis and cell cycle arrest across prostate and bladder cancer cells with associated NF-κB/Akt inactivation, BCL-2 loss, and caspase activation.","evidence":"saRNA-mediated promoter activation of PAWR, western blots for NF-κB/Akt/BCL-2/caspase/PARP, viability and apoptosis assays, and cisplatin cooperation","pmids":["26797252","34220332"],"confidence":"Low","gaps":["No direct mechanistic link showing how PAWR engages NF-κB or Akt","Pathway changes are correlative readouts, not demonstrated direct targets","Single method category without genetic confirmation"]},{"year":null,"claim":"How PAWR mechanistically couples to NF-κB and Akt signaling, and the identity and structure of its direct apoptotic binding partners, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No refined high-resolution structure of the partner-binding domain","Direct molecular partners not biochemically defined in the corpus","Causal chain from PAWR to NF-κB/Akt inactivation not established"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96IZ0","full_name":"PRKC apoptosis WT1 regulator protein","aliases":["Prostate apoptosis response 4 protein","Par-4"],"length_aa":340,"mass_kda":36.6,"function":"Pro-apoptotic protein capable of selectively inducing apoptosis in cancer cells, sensitizing the cells to diverse apoptotic stimuli and causing regression of tumors in animal models. Induces apoptosis in certain cancer cells by activation of the Fas prodeath pathway and coparallel inhibition of NF-kappa-B transcriptional activity. Inhibits the transcriptional activation and augments the transcriptional repression mediated by WT1. Down-regulates the anti-apoptotic protein BCL2 via its interaction with WT1. Also seems to be a transcriptional repressor by itself. May be directly involved in regulating the amyloid precursor protein (APP) cleavage activity of BACE1","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96IZ0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PAWR","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDOST","stoichiometry":0.2},{"gene":"PKM","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PAWR","total_profiled":1310},"omim":[{"mim_id":"609520","title":"THAP DOMAIN-CONTAINING PROTEIN 1; THAP1","url":"https://www.omim.org/entry/609520"},{"mim_id":"609492","title":"RAS ASSOCIATION DOMAIN FAMILY PROTEIN 2; RASSF2","url":"https://www.omim.org/entry/609492"},{"mim_id":"605120","title":"GROWTH/DIFFERENTIATION FACTOR 2; GDF2","url":"https://www.omim.org/entry/605120"},{"mim_id":"604333","title":"WD40 REPEAT-CONTAINING PROTEIN CIAO1; CIAO1","url":"https://www.omim.org/entry/604333"},{"mim_id":"602779","title":"COAGULATION FACTOR II RECEPTOR-LIKE 3; F2RL3","url":"https://www.omim.org/entry/602779"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Actin filaments","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Primary cilium tip","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PAWR"},"hgnc":{"alias_symbol":["par-4","PAR4"],"prev_symbol":[]},"alphafold":{"accession":"Q96IZ0","domains":[{"cath_id":"1.20.5","chopping":"270-340","consensus_level":"medium","plddt":98.1415,"start":270,"end":340}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96IZ0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96IZ0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96IZ0-F1-predicted_aligned_error_v6.png","plddt_mean":63.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PAWR","jax_strain_url":"https://www.jax.org/strain/search?query=PAWR"},"sequence":{"accession":"Q96IZ0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96IZ0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96IZ0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96IZ0"}},"corpus_meta":[{"pmid":"25803782","id":"PMC_25803782","title":"PAWR-mediated suppression of BCL2 promotes switching of 3-azido withaferin A (3-AWA)-induced autophagy to apoptosis in prostate cancer cells.","date":"2015","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/25803782","citation_count":76,"is_preprint":false},{"pmid":"32767028","id":"PMC_32767028","title":"Circ_0068655 Promotes Cardiomyocyte Apoptosis via miR-498/PAWR Axis.","date":"2020","source":"Tissue engineering and regenerative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32767028","citation_count":23,"is_preprint":false},{"pmid":"33089757","id":"PMC_33089757","title":"Circular RNA MTO1 inhibits gastric cancer progression by elevating PAWR via sponging miR-199a-3p.","date":"2020","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/33089757","citation_count":23,"is_preprint":false},{"pmid":"26797252","id":"PMC_26797252","title":"Upregulation of PAWR by small activating RNAs induces cell apoptosis in human prostate cancer cells.","date":"2016","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/26797252","citation_count":17,"is_preprint":false},{"pmid":"18085546","id":"PMC_18085546","title":"No association between prostate apoptosis response 4 gene (PAWR) in schizophrenia and mood disorders in a Japanese population.","date":"2008","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18085546","citation_count":13,"is_preprint":false},{"pmid":"34220332","id":"PMC_34220332","title":"Antitumor Activity of Small Activating RNAs Induced PAWR Gene Activation in Human Bladder Cancer Cells.","date":"2021","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34220332","citation_count":9,"is_preprint":false},{"pmid":"35251305","id":"PMC_35251305","title":"CircTRRAP Knockdown Has Cardioprotective Function in Cardiomyocytes via the Signal Regulation of miR-370-3p/PAWR Axis.","date":"2022","source":"Cardiovascular therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/35251305","citation_count":9,"is_preprint":false},{"pmid":"18281137","id":"PMC_18281137","title":"Association of missense variants of the PRKC, apoptosis, WT1, regulator (PAWR) gene with schizophrenia.","date":"2008","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/18281137","citation_count":8,"is_preprint":false},{"pmid":"36329956","id":"PMC_36329956","title":"CircHSPG2 absence weakens hypoxia-induced dysfunction in cardiomyocytes by targeting the miR-25-3p/PAWR axis.","date":"2022","source":"Cardiovascular diagnosis and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/36329956","citation_count":7,"is_preprint":false},{"pmid":"22707972","id":"PMC_22707972","title":"No association between PAWR gene polymorphisms and tardive dyskinesia in schizophrenia patients.","date":"2012","source":"Psychiatry investigation","url":"https://pubmed.ncbi.nlm.nih.gov/22707972","citation_count":6,"is_preprint":false},{"pmid":"25195896","id":"PMC_25195896","title":"Cloning, expression, purification, crystallization and preliminary crystallographic analysis of the C-terminal domain of Par-4 (PAWR).","date":"2014","source":"Acta crystallographica. Section F, Structural biology communications","url":"https://pubmed.ncbi.nlm.nih.gov/25195896","citation_count":3,"is_preprint":false},{"pmid":"20735158","id":"PMC_20735158","title":"Evidence of involvement of the human Par-4 (PAWR) gene in major depressive disorder.","date":"2010","source":"The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/20735158","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8086,"output_tokens":1094,"usd":0.020334,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7631,"output_tokens":1545,"usd":0.03839,"stage2_stop_reason":"end_turn"},"total_usd":0.058724,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"PAWR overexpression suppresses BCL2 and BECN1 expression, disrupts the BCL2-BECN1 interaction, and thereby switches autophagy to apoptosis in prostate cancer cells; pawr-KO MEFs exhibited abundant autophagy even at toxic concentrations of 3-AWA, establishing PAWR as essential for this switch.\",\n      \"method\": \"pawr knockout MEFs (loss-of-function), overexpression of EGFP-LC3B and DS-Red-BECN1, co-immunoprecipitation/interaction analysis of BCL2-BECN1, western blot for autophagy/apoptosis markers\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined phenotypic readout plus overexpression rescue and interaction disruption data, single lab\",\n      \"pmids\": [\"25803782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Upregulation of PAWR by small activating RNAs (saRNAs) targeting the PAWR promoter induces apoptosis in prostate cancer cells, associated with inactivation of the NF-κB and Akt pathways, decreased BCL-2, and activation of the caspase cascade and PARP cleavage.\",\n      \"method\": \"saRNA-mediated transcriptional activation of PAWR, western blot for pathway components (NF-κB, Akt, Bcl-2, caspase, PARP), cell viability and apoptosis assays\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, gain-of-function with pathway readouts but no direct mechanistic dissection of how PAWR engages NF-κB or Akt\",\n      \"pmids\": [\"26797252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Upregulation of PAWR by saRNAs in bladder cancer cells induces apoptosis and cell cycle arrest via inhibition of BCL-2 and inactivation of NF-κB and Akt pathways, and cooperates with cisplatin.\",\n      \"method\": \"saRNA-mediated PAWR upregulation, western blot for BCL-2, NF-κB, Akt, caspase cascade, and cell cycle proteins; cell viability and apoptosis assays\",\n      \"journal\": \"International journal of medical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method category, pharmacological cooperation without direct mechanistic dissection\",\n      \"pmids\": [\"34220332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The C-terminal domain of Par-4 (PAWR) was crystallized (rat homologue) and X-ray diffraction data collected to 3.7 Å resolution, revealing space group P41212, consistent with Par-4 being an intrinsically disordered protein that mediates interactions with apoptotic partners via its C-terminus.\",\n      \"method\": \"Protein expression, purification, and X-ray crystallography of the C-terminal domain\",\n      \"journal\": \"Acta crystallographica. Section F, Structural biology communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystallography data collected but only preliminary analysis reported (3.7 Å, no refined structure or functional validation in this report)\",\n      \"pmids\": [\"25195896\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PAWR (Par-4) is a pro-apoptotic protein that promotes apoptosis by suppressing BCL2 and BECN1 expression and disrupting the BCL2-BECN1 interaction, thereby switching autophagy to apoptosis; its pro-apoptotic signaling engages the NF-κB and Akt pathways and activates the caspase cascade, while its C-terminal domain (which mediates interactions with apoptotic partners) has been structurally characterized at preliminary resolution.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PAWR (Par-4) is a pro-apoptotic regulator that acts as a molecular switch converting autophagy to apoptosis in cancer cells [#0]. It suppresses BCL2 and BECN1 expression and disrupts the BCL2-BECN1 interaction; cells lacking PAWR fail to make this switch and instead accumulate abundant autophagy even under toxic stress, establishing PAWR as essential for the autophagy-to-apoptosis transition [#0]. Beyond this switching function, the mechanistic detail of how PAWR engages downstream signaling has not been dissected in the available corpus; its C-terminal domain, which mediates interactions with apoptotic partners, is consistent with an intrinsically disordered protein but has only been characterized at preliminary crystallographic resolution [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Addressed how Par-4 physically engages apoptotic partners by structurally characterizing its interaction-bearing region, establishing that the C-terminal domain mediates these contacts and is consistent with intrinsic disorder.\",\n      \"evidence\": \"Expression, purification, and X-ray crystallography of the rat Par-4 C-terminal domain to 3.7 Å\",\n      \"pmids\": [\"25195896\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Only preliminary diffraction data collected; no refined structure or model deposited\",\n        \"No functional validation of specific partner-binding residues in this report\",\n        \"Human PAWR domain structure not solved\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved whether PAWR is merely correlated with cell death or causally required for switching cellular fate, showing it is essential to convert cytoprotective autophagy into apoptosis by suppressing BCL2/BECN1 and disrupting their interaction.\",\n      \"evidence\": \"pawr-knockout MEFs (loss-of-function) plus overexpression rescue, BCL2-BECN1 co-immunoprecipitation, and autophagy/apoptosis marker western blots in prostate cancer cells\",\n      \"pmids\": [\"25803782\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which PAWR suppresses BCL2/BECN1 transcription or stability not defined\",\n        \"Direct vs indirect disruption of the BCL2-BECN1 interface not distinguished\",\n        \"Single-lab finding without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tested whether restoring PAWR expression is sufficient to drive apoptosis and whether this extends beyond prostate cancer, showing transcriptional upregulation induces apoptosis and cell cycle arrest across prostate and bladder cancer cells with associated NF-κB/Akt inactivation, BCL-2 loss, and caspase activation.\",\n      \"evidence\": \"saRNA-mediated promoter activation of PAWR, western blots for NF-κB/Akt/BCL-2/caspase/PARP, viability and apoptosis assays, and cisplatin cooperation\",\n      \"pmids\": [\"26797252\", \"34220332\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct mechanistic link showing how PAWR engages NF-κB or Akt\",\n        \"Pathway changes are correlative readouts, not demonstrated direct targets\",\n        \"Single method category without genetic confirmation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PAWR mechanistically couples to NF-κB and Akt signaling, and the identity and structure of its direct apoptotic binding partners, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No refined high-resolution structure of the partner-binding domain\",\n        \"Direct molecular partners not biochemically defined in the corpus\",\n        \"Causal chain from PAWR to NF-κB/Akt inactivation not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":2,"faith_pct":100.0}}