RPRM

RPRM (Reprimo) is a p53-induced tumor suppressor that operates through both cell-autonomous and non-cell-autonomous mechanisms to control cell cycle progression, apoptosis, DNA damage responses, and cell migration. In its cell-autonomous role, RPRM localizes to the cytoplasm and induces G2 arrest by inhibiting Cdc2 kinase activity and blocking nuclear translocation of cyclin B1 (PMID:10930422); upon irradiation, CDK4/6 phosphorylates RPRM at Ser98, enabling IPO11-dependent nuclear import where RPRM binds ATM and promotes its proteasomal degradation, thereby modulating DNA repair (PMID:36185355). RPRM also binds CREB and promotes its degradation after irradiation, reducing Nrf2/SCD1 signaling and triggering neuronal ferroptosis (PMID:38272326). In its non-cell-autonomous role, RPRM is secreted and engages protocadherin family receptors (FAT1, FAT4, CELSR1–3) on neighboring cells to activate the Hippo-YAP/TAZ-p73 extrinsic apoptosis pathway (PMID:39913207).

1. 2000 High

   The discovery that RPRM is a p53 target gene that arrests cells at G2 by inhibiting Cdc2 activity and blocking cyclin B1 nuclear translocation established RPRM as a downstream effector of p53 in cell cycle control.

   Evidence Ectopic expression with cell cycle analysis, Cdc2 kinase assay, and subcellular fractionation in human cell lines

   PMID:10930422

   Open questions at the time

   • Endogenous RPRM loss-of-function not tested
   • Direct binding to Cdc2/cyclin B1 not demonstrated
   • Mechanism of Cdc2 inhibition (direct vs. indirect) unresolved
2. 2009 High

   Identification of a tripartite ERα–HDAC7–FoxA1 complex that represses RPRM transcription upon estrogen signaling revealed an epigenetic mechanism for silencing this tumor suppressor in hormone-responsive contexts.

   Evidence ChIP, co-immunoprecipitation, siRNA knockdown, and HDAC7 deacetylase-dead mutant in breast cancer cells

   PMID:19917725

   Open questions at the time

   • Whether estrogen-mediated RPRM silencing contributes to breast tumorigenesis in vivo
   • Role of HDAC7 catalytic-independent repression mechanism unclear
3. 2012 Medium

   Demonstration that RPRM protein is constitutively degraded via ubiquitin-proteasome pathway and stabilized by stress, coupled with evidence that RPRM overexpression suppresses proliferation and promotes apoptosis in pituitary cells, established post-translational control of RPRM abundance and broadened its tumor suppressor function beyond G2 arrest.

   Evidence Proteasome inhibitor treatment, ubiquitination assay, caspase-3 cleavage, and clonogenic assay in pituitary tumor cell lines

   PMID:22562171

   Open questions at the time

   • E3 ubiquitin ligase for RPRM not identified
   • Whether apoptosis induction requires the same pathway as G2 arrest unresolved
4. 2016 Medium

   Finding that RPRM overexpression specifically suppresses cell migration and invasion without affecting viability or cell cycle in breast cancer cells expanded RPRM's functional repertoire to motility regulation.

   Evidence Transwell migration/invasion assays, wound healing assay, and flow cytometry in MDA-MB-231 cells

   PMID:26796959

   Open questions at the time

   • Molecular targets mediating anti-migratory effect not identified
   • No in vivo metastasis model tested
5. 2022 High

   Three independent studies in 2022 revealed: (1) RPRM undergoes CDK4/6-dependent Ser98 phosphorylation and IPO11-mediated nuclear translocation to promote ATM degradation after irradiation; (2) RPRM deletion protects hematopoietic stem cells from radiation via EGFR–STAT3–DNA-PKcs upregulation; and (3) LINC00467 recruits DNMT1 to methylate the RPRM promoter in gastric cancer. These collectively established RPRM as a central modulator of DNA damage responses and clarified epigenetic silencing mechanisms.

   Evidence Co-IP, phospho-site mutagenesis, IPO11 knockdown, proteasome inhibitors, RPRM KO mouse irradiation model, RIP/ChIP for DNMT1 at RPRM promoter

   PMID:35549646 PMID:36041213 PMID:36185355

   Open questions at the time

   • Crystal structure of RPRM–ATM interaction unknown
   • Whether CDK4/6 phosphorylation regulates functions beyond nuclear import unclear
   • LINC00467–DNMT1 mechanism validated in a single cancer type
6. 2024 High

   Identification of CREB as a direct RPRM-binding partner whose degradation after irradiation suppresses Nrf2/SCD1 and triggers neuronal ferroptosis linked RPRM to a non-apoptotic cell death pathway in the nervous system.

   Evidence Co-immunoprecipitation of RPRM–CREB, RPRM KO mouse, lipid peroxidation assay, primary neuron culture

   PMID:38272326

   Open questions at the time

   • Whether RPRM-CREB interaction is direct or scaffolded not established
   • Ferroptosis relevance beyond radiation-induced injury untested
7. 2025 High

   Discovery that RPRM is secreted and engages protocadherin receptors (FAT1, FAT4, CELSR1–3) to activate the Hippo-YAP/TAZ-p73 apoptosis axis fundamentally recast RPRM as a non-cell-autonomous tumor suppressor ligand, defining a complete p53–Reprimo–protocadherin–Hippo–p73 extrinsic signaling pathway.

   Evidence Secretion assay, receptor identification by pulldown, epistasis analysis, YAP/TAZ reporter, in vivo tumor models

   PMID:39913207

   Open questions at the time

   • Structural basis of RPRM–protocadherin binding unknown
   • Relative contribution of cell-autonomous vs. secreted RPRM to tumor suppression in vivo unresolved
8. 2025 Medium

   Conditional ERα knockout in Rprm-lineage hypothalamic neurons revealed a sex-specific role for these cells in thermoregulation, extending RPRM biology to neuroendocrine physiology.

   Evidence ReprimoCre conditional knockout mouse, core/BAT/tail temperature measurements, cell ablation in mediobasal hypothalamus

   PMID:41315012

   Open questions at the time

   • Whether RPRM protein itself has a functional role in thermoregulation or merely marks a neuronal population is unresolved
   • Downstream effectors of ERα in Rprm neurons not identified

• Key unresolved questions include: the identity of the E3 ligase(s) mediating RPRM ubiquitin-proteasomal turnover; the structural basis of RPRM interactions with ATM, CREB, and protocadherin receptors; and whether the cell-autonomous (G2 arrest, ATM degradation) and non-cell-autonomous (secreted ligand) functions are independently regulated or coordinated in vivo.
• E3 ligase for RPRM degradation unidentified
• No structural data for RPRM or its complexes
• In vivo partitioning between intracellular and secreted RPRM functions unknown