PIMREG

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).

1. 2008 High

   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

   PMID:18757745

   Open questions at the time

   • 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
2. 2008 Medium

   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

   PMID:19383357

   Open questions at the time

   • The functional consequence of CALM/AF10 relocalization for transformation is not established
   • Interaction not validated in patient leukemia material
3. 2013 High

   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

   PMID:23419774

   Open questions at the time

   • 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
4. 2016 Medium

   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

   PMID:27588395

   Open questions at the time

   • No in vivo tumor growth effect observed, limiting causal interpretation
   • Molecular basis of GLI-1 self-renewal gene regulation not defined
5. 2017 High

   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

   PMID:28667270

   Open questions at the time

   • Mechanism linking oxygen sensing to Fam64a repression unknown
   • Downstream effectors of the proliferative effect not mapped
6. 2019 High

   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

   PMID:30979686

   Open questions at the time

   • Structural basis of RHD competition not resolved
   • Whether this NF-κB role intersects with the mitotic function is unknown
7. 2019 High

   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

   PMID:31061131

   Open questions at the time

   • How PIMREG selectively enhances STAT3 at specific promoters is unclear
   • Relationship between STAT3 and NF-κB co-regulatory functions not integrated
8. 2019 Medium

   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

   PMID:31264076

   Open questions at the time

   • Direct vs indirect control of EMT transcription factors not distinguished
   • Single-lab correlative molecular readouts
9. 2021 Medium

   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

   PMID:34215720

   Open questions at the time

   • Mechanistic effectors downstream of PIMREG in prostate cells not defined
   • Single-lab study
10. 2022 Medium

    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

    PMID:35538067

    Open questions at the time

    • Domain mediating FOXM1 interaction not mapped
    • Mechanism of the autoregulatory feedback unclear
11. 2022 Medium

    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

    PMID:35878427

    Open questions at the time

    • Direct vs indirect regulation of RAD51/BRCA1/CDC25 targets not separated
    • Mechanism of HIPK2 downregulation unknown
12. 2024 Medium

    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

    PMID:38582395

    Open questions at the time

    • The ubiquitin ligase acting on S16-phosphorylated PIMREG is not identified
    • Relationship between BRSK2 turnover and APC/C-mediated mitotic turnover unresolved

• How PIMREG's mitotic/chromatin-associated function mechanistically relates to its multiple cancer transcriptional co-regulatory roles (NF-κB, STAT3, FOXM1) remains unintegrated.
• No structural model of PIMREG bound to any partner
• No unifying biochemical activity defined across its mitotic and transcriptional functions