RPRM

RPRM (Reprimo) is a p53-inducible, highly glycosylated cytoplasmic protein that functions as a tumor suppressor and cell-cycle/stress effector across multiple cellular contexts (PMID:10930422). Its canonical activity is enforcement of G2 arrest: ectopic Reprimo inhibits Cdc2 kinase activity and blocks nuclear translocation of cyclin B1, situating it within the Cdc2·cyclin B1 regulatory axis downstream of p53 (PMID:10930422). Beyond cell-cycle control, RPRM operates as an intracellular regulator of the DNA-damage and oxidative-stress response: after irradiation it is phosphorylated at Ser98 by CDK4/6 and imported into the nucleus via Importin-11, where it binds ATM and drives ATM nuclear export and proteasomal degradation, impairing DNA repair and sensitizing cells to radiation (PMID:36185355). In neurons, post-irradiation RPRM binds CREB and promotes its degradation, collapsing the downstream Nrf2/SCD1 antioxidant axis and driving iron accumulation, lipid peroxidation, and ferroptosis (PMID:38272326). RPRM is also secreted and acts extrinsically: secreted Reprimo binds protocadherin-family receptors (FAT1, FAT4, CELSR1-3) and acts upstream of the Hippo-YAP/TAZ-p73 axis to transactivate proapoptotic genes, suppressing tumors in vivo (PMID:39913207). RPRM expression is itself tightly repressed at the promoter level, both by an ERα–HDAC7–FoxA1 tripartite complex that releases RNA Pol II and depletes H3K4 methylation (PMID:19917725) and by LINC00467-directed recruitment of DNMT1, which methylates and silences the RPRM promoter in gastric cancer (PMID:35549646). A distinct physiological role is established in the brain, where ERα signaling in Rprm-lineage mediobasal hypothalamic cells governs estrogen-dependent thermoregulation in female mice (PMID:41315012).

1. 2000 High

   Established RPRM as a p53-responsive effector that enforces G2 arrest, defining its founding place in the cell-cycle checkpoint machinery.

   Evidence Ectopic expression with cell cycle analysis, Cdc2 kinase assay, and cyclin B1 localization in irradiated cells

   PMID:10930422

   Open questions at the time

   • Direct molecular target through which RPRM inhibits Cdc2 not identified
   • Mechanism linking glycosylation to function unresolved
2. 2009 High

   Resolved how RPRM transcription is silenced by hormonal signaling, identifying an ERα–HDAC7–FoxA1 complex as the repressive machinery at its promoter.

   Evidence ChIP, Co-IP, siRNA, HDAC7 deacetylase-dead mutant, and reporter assays with histone-mark analysis

   PMID:19917725

   Open questions at the time

   • Does not address RPRM protein-level function downstream of repression
   • Generalizability beyond estrogen-responsive cells untested
3. 2012 Medium

   Showed RPRM protein is constitutively destabilized by ubiquitin-proteasome turnover and that stress stabilizes it to promote apoptosis, extending its role beyond G2 arrest.

   Evidence Stable expression, proteasome inhibition, ubiquitination assays, caspase-3 cleavage, and clonogenic assays in pituitary tumor cells

   PMID:22562171

   Open questions at the time

   • E3 ligase mediating RPRM ubiquitination not identified
   • Stress-dependent stabilization mechanism unknown
4. 2012 Low

   Linked viral oncoprotein LMP-1 to engagement of the Reprimo pathway during G2/M arrest, hinting at non-p53 routes to RPRM induction.

   Evidence Ectopic LMP-1 expression with RT-PCR and flow cytometry in HEK293T

   PMID:23312294

   Open questions at the time

   • Transcriptional correlation only; no direct test that RPRM is required for LMP-1-induced arrest
   • No mechanistic dissection of induction
5. 2016 Medium

   Identified a migration/invasion-suppressive activity of RPRM distinct from its cell-cycle role, broadening its tumor-suppressor repertoire.

   Evidence Overexpression with wound-healing, Transwell invasion, and annexin V assays in MDA-MB-231 cells

   PMID:26796959

   Open questions at the time

   • Molecular mediators of the anti-migratory effect not defined
   • Single cell line
6. 2019 Low

   Placed RPRM downstream of a mutant-p53-modulating chaperone, showing HspB2 can restore RPRM expression to restrain proliferation.

   Evidence Co-IP of HspB2–p53 and western blot for RPRM in Panc-1 cells

   PMID:31692031

   Open questions at the time

   • Single Co-IP and expression measurement; RPRM is one of several reported targets
   • Causal requirement for RPRM not isolated
7. 2022 High

   Defined the regulated nuclear import of RPRM after irradiation and its action on ATM, establishing RPRM as a radiosensitizer that suppresses DNA repair.

   Evidence Reciprocal Co-IP, subcellular fractionation, Ser98 phosphomutant, CDK4/6 inhibitor, IPO11 knockdown, and in vivo irradiation

   PMID:36185355

   Open questions at the time

   • Structural basis of RPRM–ATM binding unresolved
   • E3 ligase driving ATM degradation unidentified
8. 2022 Medium

   Demonstrated in vivo that RPRM loss preserves hematopoietic stem cell regeneration via EGFR-STAT3-DNA-PKcs signaling, confirming RPRM restrains DNA repair physiologically.

   Evidence RPRM-knockout mice, HSC flow cytometry, pathway western blots, and irradiation injury model

   PMID:36041213

   Open questions at the time

   • How RPRM loss elevates EGFR expression mechanistically unclear
   • Direct versus indirect link to DNA-PKcs not separated
9. 2022 Medium

   Identified LINC00467-directed DNMT1 promoter methylation as an epigenetic silencing mechanism for RPRM in gastric cancer.

   Evidence RNA-IP/chromatin binding, methylation sequencing, and LINC00467 perturbation

   PMID:35549646

   Open questions at the time

   • Generality across tumor types untested
   • Functional consequence of RPRM silencing not directly assayed here
10. 2024 High

    Connected RPRM to neuronal ferroptosis after irradiation through CREB degradation and collapse of the Nrf2/SCD1 antioxidant axis, defining a new oxidative-stress effector function.

    Evidence RPRM-knockout mice, RPRM–CREB Co-IP, whole-brain irradiation, iron/lipid-peroxidation assays, and GPX4/Nrf2/SCD1 westerns

    PMID:38272326

    Open questions at the time

    • Mechanism by which RPRM targets CREB for degradation unresolved
    • Whether ferroptotic role extends beyond neurons unknown
11. 2025 High

    Revealed RPRM acts extracellularly as a secreted ligand for protocadherin receptors, coupling it to Hippo-YAP/TAZ-p73 proapoptotic signaling.

    Evidence Receptor-binding/Co-IP identification of FAT1/4 and CELSR1-3, Hippo reporter and proapoptotic transactivation assays, and in vivo tumor suppression

    PMID:39913207

    Open questions at the time

    • How secretion of a cytoplasmic glycoprotein is achieved not defined
    • Receptor selectivity and ligand stoichiometry unresolved
12. 2025 Medium

    Established a physiological neuroendocrine role for Rprm-lineage hypothalamic cells in estrogen-dependent thermoregulation, separate from tumor suppression.

    Evidence Reprimo-Cre conditional ERα knockout, mediobasal hypothalamic cell ablation, and core/BAT temperature telemetry in female mice

    PMID:41315012

    Open questions at the time

    • Whether RPRM protein itself, versus the lineage marker, drives thermoregulation untested
    • Molecular output of these cells not defined

• How a single glycosylated protein coordinates its cytoplasmic cell-cycle role, regulated nuclear import, ferroptosis induction, and extracellular ligand activity into one coherent regulatory logic remains unresolved.
• No structural model of RPRM
• Mechanism of RPRM secretion and processing unknown
• E3 ligases for RPRM-driven degradation of ATM and CREB unidentified