{"gene":"PIMREG","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2008,"finding":"RCS1 (PIMREG) is a substrate of APC/C (anaphase-promoting complex/cyclosome): its protein levels peak in mitosis and drop upon mitotic exit in a Cdh1-dependent manner. APC/C ubiquitinates RCS1 in vitro, and a unique N-terminal D-box is required for this ubiquitination and degradation in vivo. Loss of RCS1 accelerates metaphase-to-anaphase transition and speeds degradation of securin and cyclin B. Mitotic RCS1 associates with the NuRD chromatin-remodeling complex.","method":"In vitro ubiquitination assay, site-directed mutagenesis of D-box, live cell imaging of mitotic timing, co-immunoprecipitation with NuRD complex components, immunoblotting across cell cycle","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitination reconstitution combined with mutagenesis, in vivo cell cycle analysis, and co-IP with NuRD complex, all in a single rigorous study","pmids":["18757745"],"is_preprint":false},{"year":2008,"finding":"The CATS (PIMREG/FAM64A) protein is a novel CALM (PICALM) interacting protein that increases nuclear and specifically nucleolar localization of the leukemogenic CALM/AF10 fusion protein. CATS protein expression is cell cycle-dependent, induced by mitogens, and highly expressed in leukemia, lymphoma, and tumor cell lines but not in non-proliferating T-cells or peripheral blood lymphocytes.","method":"Co-immunoprecipitation, subcellular localization (immunofluorescence), cell cycle analysis, immunoblotting in cell lines and primary cells","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and localization experiments in single lab, two orthogonal methods","pmids":["19383357"],"is_preprint":false},{"year":2013,"finding":"CATS (PIMREG/FAM64A) physically interacts with the kinase KIS (UHMK1), confirmed by GST pull-down, co-immunoprecipitation, and co-localization. CATS is a direct phosphorylation substrate of KIS, with phosphorylation mapped to serine 131 (S131). KIS enhances the transcriptional repressor activity of CATS independent of S131 phosphorylation. KIS levels are cell cycle-dependent and inversely correlated with CATS levels. CATS and KIS together antagonize the transactivation capacity of CALM/AF10.","method":"Yeast two-hybrid screen, GST pull-down, co-immunoprecipitation, co-localization (immunofluorescence), in vitro kinase assay, phosphorylation site mutagenesis, reporter gene assay","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods including in vitro kinase assay with mutagenesis, reciprocal co-IP, and functional reporter assay in a single rigorous study","pmids":["23419774"],"is_preprint":false},{"year":2017,"finding":"Fam64a (PIMREG) is a cell cycle promoter in hypoxic fetal cardiomyocytes. It is abundantly expressed in hypoxic fetal cardiomyocyte nuclei, and expression is repressed by oxygen exposure and in postnatal cardiomyocytes. Fam64a knockdown inhibits and overexpression enhances fetal cardiomyocyte proliferation. A non-degradable Fam64a mutant indicated that proper APC/C-mediated degradation during the metaphase-to-anaphase transition is required for normal cell division.","method":"siRNA knockdown, overexpression, non-degradable mutant expression, genome-wide transcriptional analysis, immunofluorescence localization, cell proliferation assays in primary mouse fetal cardiomyocytes","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function and gain-of-function with defined proliferation phenotype, non-degradable mutant functional analysis, subcellular localization, all in primary cells with multiple orthogonal methods","pmids":["28667270"],"is_preprint":false},{"year":2019,"finding":"FAM64A (PIMREG) promotes NF-κB constitutive activation by competitively interacting with the REL homology domain (RHD) of NF-κB, displacing IκBα and disrupting the NF-κB/IκBα negative feedback loop. This sustains nuclear accumulation and transcriptional activity of NF-κB. FAM64A overexpression enhances NF-κB transactivity and promotes breast cancer aggressiveness in vitro and in vivo.","method":"Co-immunoprecipitation, EMSA, luciferase reporter assay, xenograft tumor model, MTT/soft agar/wound healing/transwell assays","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mechanistic interaction mapped by co-IP, EMSA, and reporter assay, validated in vivo with xenograft model, multiple orthogonal methods","pmids":["30979686"],"is_preprint":false},{"year":2019,"finding":"FAM64A (PIMREG) overexpression of IL-6-induced STAT3 activation and downstream target gene expression. FAM64A interacts with STAT3 in the nucleus and regulates binding of STAT3 to the promoters of its target genes. Fam64a deficiency in mice significantly impairs Th17 differentiation (but not Th1 or iTreg), attenuates EAE and DSS-induced colitis, and suppresses AOM/DSS-induced colitis-associated cancer.","method":"Co-immunoprecipitation (nuclear STAT3), chromatin immunoprecipitation (ChIP), luciferase reporter assay, Fam64a knockout mouse, flow cytometry for T cell differentiation, in vivo disease models (EAE, DSS colitis, AOM/DSS CAC)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — nuclear co-IP, ChIP, reporter assay, and in vivo knockout models with multiple orthogonal methods confirming STAT3 regulatory mechanism","pmids":["31061131"],"is_preprint":false},{"year":2016,"finding":"CATS (PIMREG/FAM64A) knockdown in U937 leukemia cells reduces proliferation, alters cell cycle progression, decreases migratory ability, and reduces clonogenicity with decreased GLI-1 self-renewal gene expression. Retroviral overexpression of murine Cats in primary bone marrow cells decreases colony formation. CATS expression decreases during erythroid, megakaryocytic, and monocytic differentiation but increases during ATRA-induced granulocytic differentiation.","method":"Lentiviral shRNA knockdown, retroviral overexpression in primary bone marrow, colony formation assay, flow cytometry cell cycle analysis, migration assay, xenotransplant model (negative result for in vivo tumor growth), immunoblotting","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined cellular phenotypes, multiple assays, single lab","pmids":["27588395"],"is_preprint":false},{"year":2019,"finding":"FAM64A (PIMREG) knockdown inhibits proliferation of breast cancer cells (MDA-MB-231 and MCF-7) and inhibits migration via impeding epithelial-mesenchymal transition (EMT), with reduced expression of N-cadherin and vimentin and EMT transcription factors Snail, Twist, and Slug.","method":"siRNA knockdown, cell counting, colony formation, flow cytometry, transwell migration assay, immunoblotting for EMT markers","journal":"Breast cancer (Tokyo, Japan)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined EMT molecular phenotype, multiple assays, single lab","pmids":["31264076"],"is_preprint":false},{"year":2021,"finding":"FAM64A (PIMREG) expression is transcriptionally upregulated by androgen receptor (AR) through direct binding of AR to the FAM64A promoter, established by chromatin immunoprecipitation. FAM64A knockdown suppresses proliferation, migration, invasion, and cell cycle progression of prostate cancer cells. FAM64A overexpression promotes these activities in androgen-dependent cells.","method":"ChIP assay (AR binding to FAM64A promoter), siRNA knockdown, overexpression, proliferation/migration/invasion assays, flow cytometry cell cycle analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — ChIP establishes direct transcriptional regulation, functional studies with knockdown/overexpression, single lab","pmids":["34215720"],"is_preprint":false},{"year":2022,"finding":"FAM64A (PIMREG) physically interacts with FOXM1 in HNSCC cells, promotes FOXM1 transcriptional activity, and modulates FOXM1 expression through an autoregulatory loop. FAM64A depletion suppresses malignant activities of HNSCC cells both in vitro and in vivo.","method":"Co-immunoprecipitation (FAM64A-FOXM1 interaction), luciferase reporter assay, siRNA knockdown, overexpression, xenograft mouse model, immunohistochemistry","journal":"International journal of oral science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and reporter assays establish physical interaction and functional consequence, in vivo validation, single lab","pmids":["35538067"],"is_preprint":false},{"year":2022,"finding":"HOXB13 transcriptionally activates PIMREG promoter (confirmed by luciferase reporter assay), and PIMREG upregulation mediates HOXB13's effects on DNA damage repair and cell cycle regulation by upregulating RAD51, BRCA1, CDC25A, CDC25B, and CDC25C and downregulating HIPK2. Downregulation of PIMREG in HOXB13-overexpressing HCC cells attenuated the HOXB13-induced phenotype.","method":"Luciferase reporter assay (HOXB13 binding PIMREG promoter), RT-qPCR, western blot, siRNA knockdown of PIMREG in HOXB13-overexpressing cells, in vivo xenograft","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter and epistasis rescue experiment, in vivo validation, single lab","pmids":["35878427"],"is_preprint":false},{"year":2024,"finding":"BRSK2 (an AMPK family kinase) phosphorylates PIMREG at serine 16 (S16) and promotes ubiquitination-mediated degradation of PIMREG, thereby modulating downstream NF-κB signaling activation. Exosomal miR-3960 from SOD1-high fibroblasts targets and inhibits BRSK2 expression in TNBC cells, leading to accumulation of S16-phosphorylated PIMREG and NF-κB activation, promoting cisplatin resistance.","method":"Phosphorylation site mapping (S16), ubiquitination assay, miRNA overexpression/inhibition, co-immunoprecipitation, immunoblotting, exosome isolation, in vitro cisplatin resistance assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation site and ubiquitination mechanism established, multiple methods, single lab","pmids":["38582395"],"is_preprint":false}],"current_model":"PIMREG (also known as FAM64A/CATS/RCS1) is a cell cycle-regulated protein that peaks in mitosis and is degraded by APC/C-Cdh1 via an N-terminal D-box during mitotic exit; it controls the timing of metaphase-to-anaphase transition, associates with the NuRD chromatin-remodeling complex, is phosphorylated at S131 by the KIS/UHMK1 kinase, and in cancer contexts promotes NF-κB activation by displacing IκBα from NF-κB's RHD domain, enhances STAT3 transcriptional activity to drive Th17 differentiation, and is regulated transcriptionally by AR and HOXB13, with its stability further modulated by BRSK2-mediated phosphorylation at S16 leading to ubiquitin-dependent degradation."},"narrative":{"mechanistic_narrative":"PIMREG (FAM64A/CATS) is a cell cycle-regulated nuclear protein that governs the timing of the metaphase-to-anaphase transition and is degraded during mitotic exit by APC/C-Cdh1 acting on a unique N-terminal D-box; loss of PIMREG accelerates anaphase onset and the degradation of securin and cyclin B, and mitotic PIMREG associates with the NuRD chromatin-remodeling complex [PMID:18757745]. Its abundance is tightly coupled to proliferation: it peaks in mitosis, is induced by mitogens, and drives cell division in contexts such as hypoxic fetal cardiomyocytes, where APC/C-mediated turnover of the protein is required for normal division [PMID:19383357, PMID:28667270]. PIMREG is a phosphorylation substrate of the kinase KIS/UHMK1 at serine 131, an interaction that enhances its transcriptional repressor activity [PMID:23419774]. Beyond the cell cycle, PIMREG acts as a transcriptional co-regulator in cancer: it competitively binds the REL homology domain of NF-κB to displace IκBα and sustain constitutive NF-κB activity [PMID:30979686], interacts with nuclear STAT3 to control STAT3 target-gene binding and drive Th17 differentiation [PMID:31061131], and physically associates with FOXM1 to amplify its transcriptional output [PMID:35538067]. Its expression is transcriptionally controlled by androgen receptor and HOXB13, the latter linking PIMREG to DNA-damage repair and cell-cycle gene programs [PMID:34215720, PMID:35878427], while its protein stability is further tuned by BRSK2-mediated phosphorylation at serine 16 that promotes ubiquitin-dependent degradation [PMID:38582395].","teleology":[{"year":2008,"claim":"Established PIMREG as a cell cycle-controlled APC/C substrate that times the metaphase-to-anaphase transition, defining its core mitotic function.","evidence":"In vitro ubiquitination reconstitution with D-box mutagenesis, live-cell imaging of mitotic timing, and co-IP with NuRD components","pmids":["18757745"],"confidence":"High","gaps":["How NuRD association contributes mechanistically to anaphase timing is not resolved","The relevant APC/C substrates downstream of PIMREG loss beyond securin/cyclin B are not defined"]},{"year":2008,"claim":"Connected PIMREG to leukemogenesis by showing it interacts with CALM (PICALM) and enhances nuclear/nucleolar localization of the CALM/AF10 fusion, with proliferation-restricted expression.","evidence":"Reciprocal co-IP, immunofluorescence localization, and cell cycle/expression analysis in cell lines and primary cells","pmids":["19383357"],"confidence":"Medium","gaps":["The functional consequence of CALM/AF10 relocalization for transformation is not established","Interaction not validated in patient leukemia material"]},{"year":2013,"claim":"Identified the kinase KIS/UHMK1 as a direct partner that phosphorylates PIMREG at S131 and modulates its transcriptional repressor activity, adding a post-translational regulatory layer.","evidence":"Yeast two-hybrid, GST pull-down, co-IP, in vitro kinase assay with site mutagenesis, and reporter assays","pmids":["23419774"],"confidence":"High","gaps":["The functional role of S131 phosphorylation is unclear since KIS enhances repressor activity independently of it","Direct DNA/chromatin targets of PIMREG repression not identified"]},{"year":2016,"claim":"Showed PIMREG supports leukemic cell proliferation, migration, and clonogenicity, but with context-dependent effects across hematopoietic differentiation lineages.","evidence":"shRNA knockdown and retroviral overexpression with colony formation, cell cycle, migration assays, and xenotransplant","pmids":["27588395"],"confidence":"Medium","gaps":["No in vivo tumor growth effect observed, limiting causal interpretation","Molecular basis of GLI-1 self-renewal gene regulation not defined"]},{"year":2017,"claim":"Demonstrated a physiological proliferative role in hypoxic fetal cardiomyocytes and that APC/C-mediated degradation of PIMREG is required for proper cell division.","evidence":"siRNA, overexpression, and non-degradable mutant in primary mouse fetal cardiomyocytes with proliferation assays and transcriptional analysis","pmids":["28667270"],"confidence":"High","gaps":["Mechanism linking oxygen sensing to Fam64a repression unknown","Downstream effectors of the proliferative effect not mapped"]},{"year":2019,"claim":"Defined a transcriptional co-regulatory function in cancer via competitive displacement of IκBα from the NF-κB RHD, sustaining constitutive NF-κB activity.","evidence":"Co-IP, EMSA, luciferase reporter, and xenograft tumor model in breast cancer cells","pmids":["30979686"],"confidence":"High","gaps":["Structural basis of RHD competition not resolved","Whether this NF-κB role intersects with the mitotic function is unknown"]},{"year":2019,"claim":"Extended PIMREG's transcriptional roles to STAT3, showing it controls STAT3 target-gene binding and is required for Th17 differentiation and inflammation-associated pathology.","evidence":"Nuclear co-IP, ChIP, reporter assays, and Fam64a knockout mouse with EAE/colitis/CAC disease models","pmids":["31061131"],"confidence":"High","gaps":["How PIMREG selectively enhances STAT3 at specific promoters is unclear","Relationship between STAT3 and NF-κB co-regulatory functions not integrated"]},{"year":2019,"claim":"Linked PIMREG to epithelial-mesenchymal transition in breast cancer through regulation of EMT markers and transcription factors.","evidence":"siRNA knockdown with proliferation, migration, and EMT marker immunoblotting","pmids":["31264076"],"confidence":"Medium","gaps":["Direct vs indirect control of EMT transcription factors not distinguished","Single-lab correlative molecular readouts"]},{"year":2021,"claim":"Identified androgen receptor as a direct transcriptional activator of PIMREG, placing it downstream of hormonal signaling in prostate cancer.","evidence":"ChIP of AR at the FAM64A promoter with knockdown/overexpression functional assays","pmids":["34215720"],"confidence":"Medium","gaps":["Mechanistic effectors downstream of PIMREG in prostate cells not defined","Single-lab study"]},{"year":2022,"claim":"Showed PIMREG interacts with FOXM1 in an autoregulatory loop driving HNSCC malignancy, broadening its set of oncogenic transcriptional partners.","evidence":"Co-IP, luciferase reporter, knockdown/overexpression, and xenograft with IHC","pmids":["35538067"],"confidence":"Medium","gaps":["Domain mediating FOXM1 interaction not mapped","Mechanism of the autoregulatory feedback unclear"]},{"year":2022,"claim":"Placed PIMREG downstream of HOXB13 as a mediator of DNA-damage repair and cell-cycle gene programs in hepatocellular carcinoma.","evidence":"Luciferase reporter of HOXB13 at PIMREG promoter, RT-qPCR/western, and epistasis rescue knockdown with xenograft","pmids":["35878427"],"confidence":"Medium","gaps":["Direct vs indirect regulation of RAD51/BRCA1/CDC25 targets not separated","Mechanism of HIPK2 downregulation unknown"]},{"year":2024,"claim":"Established BRSK2-mediated S16 phosphorylation as a stability-controlling modification that channels PIMREG to ubiquitin-dependent degradation and tunes NF-κB signaling and chemoresistance.","evidence":"Phosphosite mapping, ubiquitination assay, co-IP, and exosomal miR-3960/cisplatin resistance assays in TNBC","pmids":["38582395"],"confidence":"Medium","gaps":["The ubiquitin ligase acting on S16-phosphorylated PIMREG is not identified","Relationship between BRSK2 turnover and APC/C-mediated mitotic turnover unresolved"]},{"year":null,"claim":"How PIMREG's mitotic/chromatin-associated function mechanistically relates to its multiple cancer transcriptional co-regulatory roles (NF-κB, STAT3, FOXM1) remains unintegrated.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of PIMREG bound to any partner","No unifying biochemical activity defined across its mitotic and transcriptional functions"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,4,5,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,3,5]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,5,9]}],"complexes":["NuRD"],"partners":["UHMK1","PICALM","NFKB1","STAT3","FOXM1","BRSK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BSJ6","full_name":"Protein PIMREG","aliases":["CALM-interactor expressed in thymus and spleen","PICALM-interacting mitotic regulator","Regulator of chromosome segregation protein 1"],"length_aa":248,"mass_kda":27.5,"function":"During mitosis, may play a role in the control of metaphase-to-anaphase transition","subcellular_location":"Nucleus; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q9BSJ6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PIMREG","classification":"Not Classified","n_dependent_lines":23,"n_total_lines":1208,"dependency_fraction":0.01903973509933775},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PIMREG","total_profiled":1310},"omim":[{"mim_id":"617611","title":"PICALM-INTERACTING MITOTIC REGULATOR; PIMREG","url":"https://www.omim.org/entry/617611"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":13.0}],"url":"https://www.proteinatlas.org/search/PIMREG"},"hgnc":{"alias_symbol":["FLJ10156","FLJ10491","CATS","RCS1"],"prev_symbol":["FAM64A"]},"alphafold":{"accession":"Q9BSJ6","domains":[{"cath_id":"1.20.5","chopping":"214-248","consensus_level":"medium","plddt":81.7406,"start":214,"end":248}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BSJ6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BSJ6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BSJ6-F1-predicted_aligned_error_v6.png","plddt_mean":60.53},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PIMREG","jax_strain_url":"https://www.jax.org/strain/search?query=PIMREG"},"sequence":{"accession":"Q9BSJ6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BSJ6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BSJ6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BSJ6"}},"corpus_meta":[{"pmid":"2886082","id":"PMC_2886082","title":"DNA 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APC/C ubiquitinates RCS1 in vitro, and a unique N-terminal D-box is required for this ubiquitination and degradation in vivo. Loss of RCS1 accelerates metaphase-to-anaphase transition and speeds degradation of securin and cyclin B. Mitotic RCS1 associates with the NuRD chromatin-remodeling complex.\",\n      \"method\": \"In vitro ubiquitination assay, site-directed mutagenesis of D-box, live cell imaging of mitotic timing, co-immunoprecipitation with NuRD complex components, immunoblotting across cell cycle\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitination reconstitution combined with mutagenesis, in vivo cell cycle analysis, and co-IP with NuRD complex, all in a single rigorous study\",\n      \"pmids\": [\"18757745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The CATS (PIMREG/FAM64A) protein is a novel CALM (PICALM) interacting protein that increases nuclear and specifically nucleolar localization of the leukemogenic CALM/AF10 fusion protein. CATS protein expression is cell cycle-dependent, induced by mitogens, and highly expressed in leukemia, lymphoma, and tumor cell lines but not in non-proliferating T-cells or peripheral blood lymphocytes.\",\n      \"method\": \"Co-immunoprecipitation, subcellular localization (immunofluorescence), cell cycle analysis, immunoblotting in cell lines and primary cells\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and localization experiments in single lab, two orthogonal methods\",\n      \"pmids\": [\"19383357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CATS (PIMREG/FAM64A) physically interacts with the kinase KIS (UHMK1), confirmed by GST pull-down, co-immunoprecipitation, and co-localization. CATS is a direct phosphorylation substrate of KIS, with phosphorylation mapped to serine 131 (S131). KIS enhances the transcriptional repressor activity of CATS independent of S131 phosphorylation. KIS levels are cell cycle-dependent and inversely correlated with CATS levels. CATS and KIS together antagonize the transactivation capacity of CALM/AF10.\",\n      \"method\": \"Yeast two-hybrid screen, GST pull-down, co-immunoprecipitation, co-localization (immunofluorescence), in vitro kinase assay, phosphorylation site mutagenesis, reporter gene assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods including in vitro kinase assay with mutagenesis, reciprocal co-IP, and functional reporter assay in a single rigorous study\",\n      \"pmids\": [\"23419774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Fam64a (PIMREG) is a cell cycle promoter in hypoxic fetal cardiomyocytes. It is abundantly expressed in hypoxic fetal cardiomyocyte nuclei, and expression is repressed by oxygen exposure and in postnatal cardiomyocytes. Fam64a knockdown inhibits and overexpression enhances fetal cardiomyocyte proliferation. A non-degradable Fam64a mutant indicated that proper APC/C-mediated degradation during the metaphase-to-anaphase transition is required for normal cell division.\",\n      \"method\": \"siRNA knockdown, overexpression, non-degradable mutant expression, genome-wide transcriptional analysis, immunofluorescence localization, cell proliferation assays in primary mouse fetal cardiomyocytes\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function and gain-of-function with defined proliferation phenotype, non-degradable mutant functional analysis, subcellular localization, all in primary cells with multiple orthogonal methods\",\n      \"pmids\": [\"28667270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FAM64A (PIMREG) promotes NF-κB constitutive activation by competitively interacting with the REL homology domain (RHD) of NF-κB, displacing IκBα and disrupting the NF-κB/IκBα negative feedback loop. This sustains nuclear accumulation and transcriptional activity of NF-κB. FAM64A overexpression enhances NF-κB transactivity and promotes breast cancer aggressiveness in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, EMSA, luciferase reporter assay, xenograft tumor model, MTT/soft agar/wound healing/transwell assays\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic interaction mapped by co-IP, EMSA, and reporter assay, validated in vivo with xenograft model, multiple orthogonal methods\",\n      \"pmids\": [\"30979686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FAM64A (PIMREG) overexpression of IL-6-induced STAT3 activation and downstream target gene expression. FAM64A interacts with STAT3 in the nucleus and regulates binding of STAT3 to the promoters of its target genes. Fam64a deficiency in mice significantly impairs Th17 differentiation (but not Th1 or iTreg), attenuates EAE and DSS-induced colitis, and suppresses AOM/DSS-induced colitis-associated cancer.\",\n      \"method\": \"Co-immunoprecipitation (nuclear STAT3), chromatin immunoprecipitation (ChIP), luciferase reporter assay, Fam64a knockout mouse, flow cytometry for T cell differentiation, in vivo disease models (EAE, DSS colitis, AOM/DSS CAC)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — nuclear co-IP, ChIP, reporter assay, and in vivo knockout models with multiple orthogonal methods confirming STAT3 regulatory mechanism\",\n      \"pmids\": [\"31061131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CATS (PIMREG/FAM64A) knockdown in U937 leukemia cells reduces proliferation, alters cell cycle progression, decreases migratory ability, and reduces clonogenicity with decreased GLI-1 self-renewal gene expression. Retroviral overexpression of murine Cats in primary bone marrow cells decreases colony formation. CATS expression decreases during erythroid, megakaryocytic, and monocytic differentiation but increases during ATRA-induced granulocytic differentiation.\",\n      \"method\": \"Lentiviral shRNA knockdown, retroviral overexpression in primary bone marrow, colony formation assay, flow cytometry cell cycle analysis, migration assay, xenotransplant model (negative result for in vivo tumor growth), immunoblotting\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined cellular phenotypes, multiple assays, single lab\",\n      \"pmids\": [\"27588395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FAM64A (PIMREG) knockdown inhibits proliferation of breast cancer cells (MDA-MB-231 and MCF-7) and inhibits migration via impeding epithelial-mesenchymal transition (EMT), with reduced expression of N-cadherin and vimentin and EMT transcription factors Snail, Twist, and Slug.\",\n      \"method\": \"siRNA knockdown, cell counting, colony formation, flow cytometry, transwell migration assay, immunoblotting for EMT markers\",\n      \"journal\": \"Breast cancer (Tokyo, Japan)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined EMT molecular phenotype, multiple assays, single lab\",\n      \"pmids\": [\"31264076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FAM64A (PIMREG) expression is transcriptionally upregulated by androgen receptor (AR) through direct binding of AR to the FAM64A promoter, established by chromatin immunoprecipitation. FAM64A knockdown suppresses proliferation, migration, invasion, and cell cycle progression of prostate cancer cells. FAM64A overexpression promotes these activities in androgen-dependent cells.\",\n      \"method\": \"ChIP assay (AR binding to FAM64A promoter), siRNA knockdown, overexpression, proliferation/migration/invasion assays, flow cytometry cell cycle analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP establishes direct transcriptional regulation, functional studies with knockdown/overexpression, single lab\",\n      \"pmids\": [\"34215720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FAM64A (PIMREG) physically interacts with FOXM1 in HNSCC cells, promotes FOXM1 transcriptional activity, and modulates FOXM1 expression through an autoregulatory loop. FAM64A depletion suppresses malignant activities of HNSCC cells both in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation (FAM64A-FOXM1 interaction), luciferase reporter assay, siRNA knockdown, overexpression, xenograft mouse model, immunohistochemistry\",\n      \"journal\": \"International journal of oral science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and reporter assays establish physical interaction and functional consequence, in vivo validation, single lab\",\n      \"pmids\": [\"35538067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HOXB13 transcriptionally activates PIMREG promoter (confirmed by luciferase reporter assay), and PIMREG upregulation mediates HOXB13's effects on DNA damage repair and cell cycle regulation by upregulating RAD51, BRCA1, CDC25A, CDC25B, and CDC25C and downregulating HIPK2. Downregulation of PIMREG in HOXB13-overexpressing HCC cells attenuated the HOXB13-induced phenotype.\",\n      \"method\": \"Luciferase reporter assay (HOXB13 binding PIMREG promoter), RT-qPCR, western blot, siRNA knockdown of PIMREG in HOXB13-overexpressing cells, in vivo xenograft\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter and epistasis rescue experiment, in vivo validation, single lab\",\n      \"pmids\": [\"35878427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BRSK2 (an AMPK family kinase) phosphorylates PIMREG at serine 16 (S16) and promotes ubiquitination-mediated degradation of PIMREG, thereby modulating downstream NF-κB signaling activation. Exosomal miR-3960 from SOD1-high fibroblasts targets and inhibits BRSK2 expression in TNBC cells, leading to accumulation of S16-phosphorylated PIMREG and NF-κB activation, promoting cisplatin resistance.\",\n      \"method\": \"Phosphorylation site mapping (S16), ubiquitination assay, miRNA overexpression/inhibition, co-immunoprecipitation, immunoblotting, exosome isolation, in vitro cisplatin resistance assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation site and ubiquitination mechanism established, multiple methods, single lab\",\n      \"pmids\": [\"38582395\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PIMREG (also known as FAM64A/CATS/RCS1) is a cell cycle-regulated protein that peaks in mitosis and is degraded by APC/C-Cdh1 via an N-terminal D-box during mitotic exit; it controls the timing of metaphase-to-anaphase transition, associates with the NuRD chromatin-remodeling complex, is phosphorylated at S131 by the KIS/UHMK1 kinase, and in cancer contexts promotes NF-κB activation by displacing IκBα from NF-κB's RHD domain, enhances STAT3 transcriptional activity to drive Th17 differentiation, and is regulated transcriptionally by AR and HOXB13, with its stability further modulated by BRSK2-mediated phosphorylation at S16 leading to ubiquitin-dependent degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PIMREG (FAM64A/CATS) is a cell cycle-regulated nuclear protein that governs the timing of the metaphase-to-anaphase transition and is degraded during mitotic exit by APC/C-Cdh1 acting on a unique N-terminal D-box; loss of PIMREG accelerates anaphase onset and the degradation of securin and cyclin B, and mitotic PIMREG associates with the NuRD chromatin-remodeling complex [#0]. Its abundance is tightly coupled to proliferation: it peaks in mitosis, is induced by mitogens, and drives cell division in contexts such as hypoxic fetal cardiomyocytes, where APC/C-mediated turnover of the protein is required for normal division [#1, #3]. PIMREG is a phosphorylation substrate of the kinase KIS/UHMK1 at serine 131, an interaction that enhances its transcriptional repressor activity [#2]. Beyond the cell cycle, PIMREG acts as a transcriptional co-regulator in cancer: it competitively binds the REL homology domain of NF-\\u03baB to displace I\\u03baB\\u03b1 and sustain constitutive NF-\\u03baB activity [#4], interacts with nuclear STAT3 to control STAT3 target-gene binding and drive Th17 differentiation [#5], and physically associates with FOXM1 to amplify its transcriptional output [#9]. Its expression is transcriptionally controlled by androgen receptor and HOXB13, the latter linking PIMREG to DNA-damage repair and cell-cycle gene programs [#8, #10], while its protein stability is further tuned by BRSK2-mediated phosphorylation at serine 16 that promotes ubiquitin-dependent degradation [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established PIMREG as a cell cycle-controlled APC/C substrate that times the metaphase-to-anaphase transition, defining its core mitotic function.\",\n      \"evidence\": \"In vitro ubiquitination reconstitution with D-box mutagenesis, live-cell imaging of mitotic timing, and co-IP with NuRD components\",\n      \"pmids\": [\"18757745\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NuRD association contributes mechanistically to anaphase timing is not resolved\", \"The relevant APC/C substrates downstream of PIMREG loss beyond securin/cyclin B are not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected PIMREG to leukemogenesis by showing it interacts with CALM (PICALM) and enhances nuclear/nucleolar localization of the CALM/AF10 fusion, with proliferation-restricted expression.\",\n      \"evidence\": \"Reciprocal co-IP, immunofluorescence localization, and cell cycle/expression analysis in cell lines and primary cells\",\n      \"pmids\": [\"19383357\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The functional consequence of CALM/AF10 relocalization for transformation is not established\", \"Interaction not validated in patient leukemia material\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified the kinase KIS/UHMK1 as a direct partner that phosphorylates PIMREG at S131 and modulates its transcriptional repressor activity, adding a post-translational regulatory layer.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, co-IP, in vitro kinase assay with site mutagenesis, and reporter assays\",\n      \"pmids\": [\"23419774\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The functional role of S131 phosphorylation is unclear since KIS enhances repressor activity independently of it\", \"Direct DNA/chromatin targets of PIMREG repression not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed PIMREG supports leukemic cell proliferation, migration, and clonogenicity, but with context-dependent effects across hematopoietic differentiation lineages.\",\n      \"evidence\": \"shRNA knockdown and retroviral overexpression with colony formation, cell cycle, migration assays, and xenotransplant\",\n      \"pmids\": [\"27588395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo tumor growth effect observed, limiting causal interpretation\", \"Molecular basis of GLI-1 self-renewal gene regulation not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated a physiological proliferative role in hypoxic fetal cardiomyocytes and that APC/C-mediated degradation of PIMREG is required for proper cell division.\",\n      \"evidence\": \"siRNA, overexpression, and non-degradable mutant in primary mouse fetal cardiomyocytes with proliferation assays and transcriptional analysis\",\n      \"pmids\": [\"28667270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking oxygen sensing to Fam64a repression unknown\", \"Downstream effectors of the proliferative effect not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a transcriptional co-regulatory function in cancer via competitive displacement of I\\u03baB\\u03b1 from the NF-\\u03baB RHD, sustaining constitutive NF-\\u03baB activity.\",\n      \"evidence\": \"Co-IP, EMSA, luciferase reporter, and xenograft tumor model in breast cancer cells\",\n      \"pmids\": [\"30979686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of RHD competition not resolved\", \"Whether this NF-\\u03baB role intersects with the mitotic function is unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended PIMREG's transcriptional roles to STAT3, showing it controls STAT3 target-gene binding and is required for Th17 differentiation and inflammation-associated pathology.\",\n      \"evidence\": \"Nuclear co-IP, ChIP, reporter assays, and Fam64a knockout mouse with EAE/colitis/CAC disease models\",\n      \"pmids\": [\"31061131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PIMREG selectively enhances STAT3 at specific promoters is unclear\", \"Relationship between STAT3 and NF-\\u03baB co-regulatory functions not integrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked PIMREG to epithelial-mesenchymal transition in breast cancer through regulation of EMT markers and transcription factors.\",\n      \"evidence\": \"siRNA knockdown with proliferation, migration, and EMT marker immunoblotting\",\n      \"pmids\": [\"31264076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect control of EMT transcription factors not distinguished\", \"Single-lab correlative molecular readouts\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified androgen receptor as a direct transcriptional activator of PIMREG, placing it downstream of hormonal signaling in prostate cancer.\",\n      \"evidence\": \"ChIP of AR at the FAM64A promoter with knockdown/overexpression functional assays\",\n      \"pmids\": [\"34215720\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic effectors downstream of PIMREG in prostate cells not defined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed PIMREG interacts with FOXM1 in an autoregulatory loop driving HNSCC malignancy, broadening its set of oncogenic transcriptional partners.\",\n      \"evidence\": \"Co-IP, luciferase reporter, knockdown/overexpression, and xenograft with IHC\",\n      \"pmids\": [\"35538067\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain mediating FOXM1 interaction not mapped\", \"Mechanism of the autoregulatory feedback unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed PIMREG downstream of HOXB13 as a mediator of DNA-damage repair and cell-cycle gene programs in hepatocellular carcinoma.\",\n      \"evidence\": \"Luciferase reporter of HOXB13 at PIMREG promoter, RT-qPCR/western, and epistasis rescue knockdown with xenograft\",\n      \"pmids\": [\"35878427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect regulation of RAD51/BRCA1/CDC25 targets not separated\", \"Mechanism of HIPK2 downregulation unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established BRSK2-mediated S16 phosphorylation as a stability-controlling modification that channels PIMREG to ubiquitin-dependent degradation and tunes NF-\\u03baB signaling and chemoresistance.\",\n      \"evidence\": \"Phosphosite mapping, ubiquitination assay, co-IP, and exosomal miR-3960/cisplatin resistance assays in TNBC\",\n      \"pmids\": [\"38582395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The ubiquitin ligase acting on S16-phosphorylated PIMREG is not identified\", \"Relationship between BRSK2 turnover and APC/C-mediated mitotic turnover unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PIMREG's mitotic/chromatin-associated function mechanistically relates to its multiple cancer transcriptional co-regulatory roles (NF-\\u03baB, STAT3, FOXM1) remains unintegrated.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of PIMREG bound to any partner\", \"No unifying biochemical activity defined across its mitotic and transcriptional functions\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 4, 5, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 3, 5]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 5, 9]}\n    ],\n    \"complexes\": [\"NuRD\"],\n    \"partners\": [\"UHMK1\", \"PICALM\", \"NFKB1\", \"STAT3\", \"FOXM1\", \"BRSK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}