Affinage

RBL2

Retinoblastoma-like protein 2 · UniProt Q08999

Length
1139 aa
Mass
128.4 kDa
Annotated
2026-06-10
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RBL2/p130 is a nuclear pocket-protein cell-cycle repressor that enforces quiescence and senescence by assembling the DREAM repressor complex with E2F4 and the MuvB subunits LIN-9/37/52/54 and RBBP4, which binds over 800 promoters in G0 to silence E2F target genes; in S phase the MuvB module dissociates from p130 and switches to MYB (PMID:17531812). Its repressive output extends to specific gene programs including Aurora kinase A/B pathway genes via the DREAM/LIN37 module (PMID:35058503), the PARP1 promoter through an E2F4-RBL2-HDAC1-BRM(SWI/SNF) complex that compacts chromatin (PMID:28842672), and paracrine WNT ligands within an E2F/RB axis (PMID:38678032), while it also represses VEGF (PMID:11212232), FGFR1 (PMID:32973083), and the Dnmt methyltransferases (PMID:18311151). p130 functions as the dominant pocket protein driving p53-p21-dependent senescence, accumulating downstream of p21 or p16 to repress cyclin A and block S-phase re-entry (PMID:19648966, PMID:16123778). Its activity is set by a dense post-translational network: cell-cycle-regulated phosphorylation peaks at S-phase onset (PMID:8567757), GSK3 phosphorylation stabilizes the protein (PMID:15456871), AKT1 phosphorylates Ser941 in the pocket domain to destabilize it and limit nuclear accumulation (PMID:29606701), PP2A dephosphorylates C-terminal NLS sites to protect p130 from ubiquitination and enable importin-alpha-mediated nuclear import (PMID:12915404, PMID:16206244), and the SCF-cyclin F E3 ligase binds a site in the pocket-domain linker to ubiquitinate and degrade it (PMID:34851822). Nucleocytoplasmic shuttling is governed by multiple C-terminal and Loop-region NLSs and an N-terminal cytoplasmic-retention domain, and natural NLS-disrupting mutations that mislocalize p130 to the cytoplasm abolish its tumor-suppressor cell-cycle-arrest activity (PMID:11756542, PMID:10667591). RBL2 transcription is itself controlled by CTCF (antagonized by BORIS), AP-2, Utx-mediated H3K27 demethylation, HOXB9, and miRNA targeting of its 3'UTR (miR-290, miR-17, miR-93) (PMID:21325284, PMID:11420667, PMID:20650264, PMID:35182659, PMID:18311151, PMID:25183046).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1995 Medium

    Established that p130 is a nuclear phosphoprotein whose phosphorylation is cell-cycle-coupled and targeted by viral oncoprotein-associated kinases, framing it as a regulated cell-cycle component rather than a static protein.

    Evidence Immunocytochemistry, phosphatase treatment, and biochemical cell-cycle analysis with a spacer-region antibody

    PMID:8567757

    Open questions at the time
    • Specific kinases and phosphosites not yet defined
    • Functional consequence of phosphorylation peak not established
  2. 2000 High

    Showed that an intact NLS is essential for p130 nuclear localization and tumor-suppressor function, linking subcellular localization directly to cell-cycle-arrest activity.

    Evidence SSCP/sequencing of tumors, NLS site-directed mutagenesis, immunocytochemistry, and flow cytometry

    PMID:10667591

    Open questions at the time
    • Import machinery not identified at this stage
    • Did not address upstream regulation of NLS
  3. 2000 Medium

    Identified a CDE/CHR promoter element that imposes cell-cycle-dependent repression of the RBL2 gene itself, revealing autoregulatory transcriptional control of p130 levels.

    Evidence In vivo genomic footprinting, EMSA, and luciferase reporters with mutagenesis (mouse promoter)

    PMID:10760507

    Open questions at the time
    • Identity of CDE/CHR-binding complexes not determined
    • Element studied in mouse promoter only
  4. 2002 High

    Mapped the determinants of p130 nucleocytoplasmic shuttling, defining multiple NLSs, a cytoplasmic-retention N-terminus, and the pocket domain as sufficient for nuclear import and E2F-dependent growth arrest.

    Evidence Heterokaryon fusion, microinjection, and NLS mutagenesis in transfected cells

    PMID:11756542

    Open questions at the time
    • Signals controlling shuttling dynamics not linked to upstream pathways here
    • Import receptor not yet identified
  5. 2003 High

    Defined PP2A as a stabilizing regulator that binds and dephosphorylates p130 at its C-terminal NLS, protecting it from ubiquitin-proteasomal degradation and linking dephosphorylation to growth suppression.

    Evidence Reciprocal Co-IP, GST pulldown, PP2A siRNA, mutant panel, and ubiquitination assays with ATRA growth readout

    PMID:12915404

    Open questions at the time
    • Specific dephosphorylated residues only partially mapped
    • Connection to import machinery not yet shown
  6. 2004 High

    Demonstrated that GSK3 phosphorylation of p130 during G0 promotes its stability without altering E2F4 or cyclin binding, distinguishing stabilizing from inactivating phosphorylation events.

    Evidence GSK3 inhibitors, site-specific mutants, and phospho-specific antibodies in quiescent cells

    PMID:15456871

    Open questions at the time
    • Mechanism by which phosphorylation confers stability not resolved
    • Interplay with PP2A and CDK sites not integrated
  7. 2006 Medium

    Connected PP2A-mediated NLS dephosphorylation to importin-alpha binding, providing a mechanistic route from phosphatase activity to nuclear translocation and G1 arrest.

    Evidence Co-IP, truncation/NLS mutants, and growth assays under ATRA in ovarian carcinoma cells

    PMID:16206244

    Open questions at the time
    • Direct importin-alpha-p130 interaction shown in one system
    • Kinase counteracting PP2A at NLS not identified
  8. 2006 Medium

    Showed that p53 selectively cooperates with p130 to drive senescence via a pocket-protein switch and cyclin A repression, identifying p130 as the effector arm of p53-induced arrest.

    Evidence Temperature-sensitive p53, stable transfection, and cyclin-based cell-cycle analysis in p16-null glioma cells

    PMID:16123778

    Open questions at the time
    • Generality beyond p16-null glioma context untested here
    • How p53 triggers the pocket-protein switch not defined
  9. 2009 High

    Established p130 as the dominant pocket protein for p53-p21-dependent senescence, with p16 and p21 converging on p130 accumulation and its knockdown permitting S-phase re-entry.

    Evidence RNAi epistasis, p21/p16 overexpression, and cyclin/DNA-synthesis readouts across multiple cell lines

    PMID:19648966

    Open questions at the time
    • Molecular basis of p130 accumulation downstream of p21 not fully defined
    • Did not resolve DREAM-level mechanism
  10. 2007 High

    Defined the DREAM complex architecture, showing p130 partners with E2F4 and MuvB subunits to repress >800 promoters in G0 and that S-phase entry triggers MuvB dissociation and a switch to MYB.

    Evidence Mass spectrometry, ChIP-chip, bioinformatics, and Co-IP

    PMID:17531812

    Open questions at the time
    • Signal triggering MuvB-p130 dissociation not mechanistically resolved
    • Promoter-selectivity determinants within the >800 targets unclear
  11. 2008 High

    Revealed a developmental/epigenetic role: miR-290-mediated silencing of Rbl2 sustains Dnmt expression, so Rbl2 accumulation in Dicer1-null cells causes DNA hypomethylation and telomere recombination.

    Evidence Dicer1-knockout cells, Dnmt rescue, miR-290 re-expression, and 3'UTR luciferase reporters

    PMID:18311151

    Open questions at the time
    • Mechanism by which Rbl2 represses Dnmt genes not detailed
    • Relationship to DREAM repression not addressed
  12. 2017 Medium

    Showed that disrupting the RBL2-E2F4 promoter complex (via miR-17-5p) flips E2F activity from repression to activation, demonstrating that the complex's integrity gates proliferation.

    Evidence Co-IP, ChIP, luciferase reporters, and miRNA gain/loss with flow cytometry in pancreatic cancer cells

    PMID:28987387

    Open questions at the time
    • Single cancer-cell context
    • Did not dissect full DREAM/MuvB involvement
  13. 2018 High

    Identified AKT1 as a kinase that directly phosphorylates p130 at Ser941 in the pocket domain to destabilize it and limit nuclear levels, defining a survival-signaling input that restrains p130-dependent apoptosis.

    Evidence Co-IP, in vitro kinase assay, S941A mutagenesis, AKT inhibition, and RBL2-silencing rescue across cancer lines

    PMID:29606701

    Open questions at the time
    • Link between Ser941 phosphorylation and degradation machinery not defined
    • Interplay with PP2A/cyclin F not integrated
  14. 2021 High

    Defined the SCF-cyclin F E3 ligase as the degradation pathway for p130, mapping a cyclin F-binding site in the pocket-domain linker whose mutation impairs proliferation and cell-cycle gene expression.

    Evidence CRISPR screens, direct binding and ubiquitination assays, mutagenesis, and quantitative imaging

    PMID:34851822

    Open questions at the time
    • Coordination with AKT/PP2A phospho-regulation not resolved
    • Cell-cycle timing of degradation only partially mapped
  15. 2022 Medium

    Extended DREAM target scope to therapy-relevant programs, showing p53/RBL2/LIN37-dependent repression of Aurora kinase A/B genes controls paclitaxel and radiation sensitivity.

    Evidence siRNA knockdown of RBL2/LIN37/p53 with expression and drug/radiation-response assays in NSCLC

    PMID:35058503

    Open questions at the time
    • Direct DREAM occupancy of AURKA/B promoters not shown here
    • Single-lab cell-line data
  16. 2022 Medium

    Placed RBL2 upstream of FGFR1 in vivo, showing RBL2 loss induces FGFR1 and that Fgfr1 deletion suppresses tumorigenesis specifically when Rbl2 is lost, defining a tumor-suppressor effector pathway.

    Evidence Fgfr1-knockout cross with Rbl2-deficient SCLC mouse model plus cell-line restoration

    PMID:32973083

    Open questions at the time
    • Whether FGFR1 repression is direct DREAM-mediated not shown
    • Mechanism of derepression upon RBL2 loss unclear
  17. 2024 Medium

    Showed the E2F1/4-pRb/RBL2 axis controls paracrine WNT ligand expression via GCN5-deposited H3K9ac, linking p130 repression to cancer stem-cell self-renewal and chemoresistance.

    Evidence Secretome proteomics, genetic E2F/RB manipulation, WNT expression, and epigenetic inhibitor screens in PDAC/breast models

    PMID:38678032

    Open questions at the time
    • Direct RBL2 occupancy at WNT promoters not detailed
    • Relative contributions of pRb vs RBL2 not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple, opposing post-translational inputs (CDK/AKT phosphorylation, GSK3-mediated stabilization, PP2A dephosphorylation, SCF-cyclin F degradation) are integrated to set p130 abundance, localization, and DREAM occupancy at specific promoters across the cell cycle remains unresolved.
  • No unified model coordinating phospho-regulation with ubiquitination timing
  • Determinants of DREAM promoter selectivity unknown
  • No structural model of the p130 pocket-domain regulatory linker bound by its regulators

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
CCNFE2F4LIN37LIN52LIN54LIN9PP2ARBBP4
Complex memberships
DREAM complexE2F4-RBL2-HDAC1-BRM(SWI/SNF) repressor complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 RBL2/p130 forms a multisubunit protein complex called DREAM (DP, RB-like, E2F, and MuvB) containing mammalian homologs of C. elegans synMuvB proteins (LIN-9, LIN-37, LIN-52, LIN-54, LIN-53/RBBP4) and E2F4. DREAM binds to more than 800 human promoters in G0 and is required for repression of E2F target genes. In S phase, MuvB proteins dissociate from p130 and associate with MYB instead. Proteomics (mass spectrometry), ChIP-chip genomics, bioinformatics, co-immunoprecipitation Molecular cell High 17531812
1995 RBL2/p130 is a nuclear phosphoprotein; its phosphorylation is cell cycle regulated, reaching a peak at the onset of S-phase. It is one of the major targets of E1A viral oncoprotein-associated kinase activity, similar to p107. Immunocytochemistry, phosphatase treatment, biochemical characterization with polyclonal antibody against the spacer region Journal of cellular biochemistry Medium 8567757
2002 RBL2/p130 shuttles between nucleus and cytoplasm. Two independent nuclear localization signals (NLS) were identified in the C-terminus of p130, and an additional NLS was mapped within the unique Loop region. An N-terminal domain confers cytoplasmic localization. The intact pocket domain is sufficient for nuclear translocation. Removal of the entire N-terminus did not affect the ability of p130 to interact with E2F or to induce growth arrest. Heterokaryon fusion assay, transient transfection, microinjection, NLS mutagenesis Molecular and cellular biology High 11756542
2004 Glycogen synthase kinase 3 (GSK3) phosphorylates RBL2/p130 during G0 quiescence at consensus GSK3 sites. GSK3 phosphorylation of p130 contributes to its stability but does not affect its ability to interact with E2F4 or cyclins. GSK3 small-molecule inhibitors, site-specific p130 mutants, phospho-specific antibodies Molecular and cellular biology High 15456871
2003 Protein phosphatase 2A (PP2A) associates with RBL2/p130 and dephosphorylates it, protecting p130 from ubiquitination and proteasomal degradation. This association is mediated by the NLS sequences in the C-terminus of Rb2/p130. CDK4 phosphorylation sites on p130 are among the candidate sites dephosphorylated by PP2A. ATRA-mediated growth suppression of ovarian carcinoma cells requires this PP2A–Rb2/p130 interaction. Co-immunoprecipitation, GST pulldown, siRNA knockdown of PP2A, Rb2/p130 mutant panel, ubiquitination assays The Journal of biological chemistry High 12915404
2006 PP2A catalytic subunit (PP2Ac) binds directly to the NLS sequences in the C-terminus of Rb2/p130. ATRA treatment leads to hypophosphorylation of PP2Ac (increased PP2A activity), which dephosphorylates the NLS of Rb2/p130, enabling importin alpha binding and nuclear translocation of Rb2/p130, leading to G1 arrest. Co-immunoprecipitation, truncation and NLS mutant transfection, cell growth assays, ATRA treatment Journal of cellular physiology Medium 16206244
2000 Naturally occurring mutations disrupting the putative bipartite nuclear localization signal (NLS) of RBL2/p130 cause aberrant cytoplasmic localization of the protein. Site-directed mutagenesis of NLS residues markedly reduced biological activity (measured by cell cycle analysis), establishing the NLS as essential for p130 tumor suppressor function. SSCP, sequencing, site-directed mutagenesis, transfection, immunocytochemistry, Western blot, flow cytometry Cancer research High 10667591
1999 RBL2/p130-mediated inhibition of smooth muscle cell proliferation correlates with its ability to bind and sequester E2F transcription factors. Adenovirus-mediated arterial delivery of RBL2/p130 significantly reduced neointimal hyperplasia in a rat carotid artery restenosis model. Adenoviral gene delivery, rat carotid artery angioplasty model, in vitro proliferation assay, E2F binding assays Circulation research Medium 10571534
2001 Overexpression of RBL2/p130 downregulates vascular endothelial growth factor (VEGF) expression both in vitro and in vivo, and inhibits angiogenesis in vivo, using a tetracycline-regulated expression system and retroviral/adenoviral delivery. Tet-regulated gene expression, retroviral and adenoviral gene delivery, VEGF protein measurement, in vivo angiogenesis assay Cancer research Medium 11212232
2009 Rb2/p130 is the dominant pocket protein mediating cellular senescence in a p53-p21-dependent manner. Knockdown of Rb2/p130 by RNAi allowed re-entry into S phase (cyclin A expression and DNA synthesis restored) in senescent cells. Overexpression of either p21 or p16 converged on Rb2/p130 accumulation to induce senescence. p53- or p21-negative cells failed to accumulate Rb2/p130 upon DNA damage and did not enter senescence. RNAi knockdown, cell cycle analysis (cyclin expression), overexpression of p21/p16, comparison across multiple cell lines Oncogene High 19648966
2006 p53 cooperates selectively with p130/Rb2 to induce cellular senescence. Activation of temperature-sensitive p53 in p16-negative C6 glioma cells induces a switch in pocket protein expression from pRb/p107 to p130/Rb2, arresting cells in late G1/early S-phase. Maintenance of arrest depends on p130/Rb2 repressing cyclin A. Temperature-sensitive p53 mutant, stable transfection, cell cycle analysis (cyclin expression), immunofluorescence Cell death and differentiation Medium 16123778
2000 A CDE/CHR-like element in the mouse RBL2/p130 gene promoter mediates cell cycle-dependent transcriptional repression. This bipartite element makes major groove DNA contacts with proteins detectable in vivo, and inactivation of either CDE or CHR strongly upregulates p130 promoter activity in proliferating cells where endogenous p130 is nearly undetectable. Two different protein complexes bind independently to the CDE and CHR elements. Promoter deletion analysis, in vivo genomic footprinting, EMSA, luciferase reporter assays, site-directed mutagenesis FEBS letters Medium 10760507
2001 The AP-2 transcription factor directly binds a KER1 palindromic sequence in the Rb2/p130 promoter and activates its transcription. AP-2 overexpression increased Rb2/p130 mRNA and protein; Rb2/p130 acts as a critical effector downstream of AP-2 in sustaining ectodermal/neuronal differentiation in PC12 cells. Promoter analysis, EMSA (in vitro AP-2 binding), transfection/overexpression, AP-2B dominant negative, NGF differentiation model Oncogene Medium 11420667
2001 HIV-1 Tat protein physically binds to pRb2/p130 in vitro and in vivo binding assays, potentially inactivating its oncosuppressive properties and inducing expression of cell cycle genes including p107, cyclin A, and cyclin B. In vitro and in vivo binding assays (co-immunoprecipitation) Human pathology Medium 12196924
2001 nm23 modulates the expression of Rb2/p130 gene during NGF-induced PC12 cell differentiation. nm23-H1 mutants defective in inhibiting invasion downregulate Rb2/p130 expression and inhibit NGF-induced differentiation, establishing an interplay between nm23 and Rb2/p130 in driving neuronal differentiation. Transfection of nm23 mutants, Western blot, neurite outgrowth assay, [3H]thymidine incorporation Cell death and differentiation Medium 11423907
2017 RBL2 interacts with the transcription factor E2F4 and binds to promoter regions of E2F target genes to repress them. Disruption of the RBL2/E2F4 complex by miR-17-5p overexpression shifts E2F activity from gene repression to activation, inducing cell cycle entry and proliferation in pancreatic cancer cells. Co-immunoprecipitation, ChIP, luciferase reporter assay, flow cytometry, miRNA overexpression/knockdown Cancer letters Medium 28987387
2018 RBL2/p130 is a direct substrate of AKT kinase. AKT1 physically interacts with RBL2/p130 and phosphorylates it at Ser941 in the pocket domain; mutation of Ser941 to Ala abolishes AKT-mediated phosphorylation. Pharmacological AKT inhibition impairs RBL2 Ser941 phosphorylation, increases RBL2 stability and nuclear levels, and induces RBL2-dependent apoptosis in lung cancer and mesothelioma cells. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (S941A), AKT inhibitor treatment, RBL2 silencing rescue experiments, flow cytometry Oncogene High 29606701
2021 RBL2/p130 is a direct substrate of the SCF-cyclin F E3 ubiquitin ligase complex. Cyclin F binds a regulatory site in the flexible linker of the p130 pocket domain, and this site mediates binding, ubiquitination, and stability of p130. Expression of a ubiquitination-resistant p130 mutant severely impairs cell proliferation and cell cycle gene expression. CRISPR/Cas9 genetic screens, direct binding assay, ubiquitination assay, mutagenesis, quantitative iterative immunofluorescent imaging, transcript analysis eLife High 34851822
2010 Utx histone H3K27 demethylase directly regulates RBL2/p130 expression. Utx associates with the Rbl2 promoter, removes repressive H3K27 trimethylation, and increases active H3K4 trimethylation. Endogenous Utx is recruited to the Rbl2 promoter as shown by ChIP after siRNA knockdown. Chromatin immunoprecipitation (ChIP), siRNA knockdown, ectopic expression, histone methylation analysis Biochemical and biophysical research communications Medium 20650264
2011 CTCF directly controls RBL2/p130 gene expression in lung fibroblasts by binding the Rb2/p130 promoter and establishing a local chromatin organization that governs transcriptional activity. In lung cancer cells, BORIS (a CTCF paralogue) competes with CTCF at the Rb2/p130 promoter, altering the chromatin state and impairing CTCF-mediated activation of Rb2/p130. ChIP, promoter binding assays, chromatin organization analysis, BORIS/CTCF overexpression, lung cancer cell proliferation assays Molecular cancer research Medium 21325284
2011 Loss of Rbl2/p130 in adult mice results in unscheduled proliferation of cochlear supporting cells and supernumerary inner ear hair cells and supporting cells in apical regions, with downregulation of cell cycle inhibitors, establishing p130 as a regulator of mitotic quiescence in cochlear supporting and hair cells. p130 knockout mouse analysis, cochlear histology, BrdU incorporation, cell cycle inhibitor expression analysis The Journal of neuroscience Medium 21677172
2010 p130/Rb2 and Mirk/dyrk1B cooperatively mediate G0 quiescent arrest in ovarian cancer cells. Depletion of p130/Rb2 reduced the G0 fraction, increased cisplatin sensitivity, and reduced Mirk levels. p130/Rb2 forms complexes with E2F4 in G0-arrested cells. siRNA depletion, flow cytometry (G0 fraction), co-immunoprecipitation (p130/E2F4 complex), cell viability assays International journal of cancer Medium 20857490
2022 RBL2/p130 represses FGFR1 expression; loss of RBL2 induces FGFR1 expression, and restoration of RBL2 represses it. In a mouse SCLC model, Fgfr1 knockout suppressed tumor development when Rbl2 was lost but not when Rbl2 was wild-type, placing RBL2 upstream of FGFR1 in a regulatory pathway. Fgfr1 knockout mouse crossed with Rbl2-deficient SCLC model, RBL2 restoration in cancer cell lines, gene expression analysis Cancer research Medium 32973083
2022 RBL2/p130 is a component of the DREAM repressor complex that represses Aurora kinase A/B pathway genes in a p53-dependent manner. Knockdown of p53, RBL2, or the DREAM component LIN37 increased AURKA/B pathway gene expression and reduced paclitaxel and radiation sensitivity in NSCLC cells. siRNA knockdown of RBL2, LIN37, p53; gene expression analysis; drug/radiation sensitivity assays Scientific reports Medium 35058503
2017 Downregulation of PARP1 in monocytes during differentiation-associated cell cycle exit involves assembly of an E2F4-RBL2-HDAC1-BRM(SWI/SNF) repressor complex at the PARP1 promoter that deacetylates nucleosomes and compacts chromatin. Silencing of RBL2 restored PARP1 expression and increased transcription of pluripotency factors (POU5F1, SOX2, NANOG) in monocytes. ChIP, RNAi knockdown, HDAC/EZH2 inhibitor treatment, reporter assays, chromatin compaction analysis Scientific reports Medium 28842672
2024 The E2F1/4-pRb/RBL2 axis regulates WNT ligand expression (WNT7A, WNT7B, WNT10A, WNT4) in a cell-autonomous manner: E2F1 and E2F4 induce WNT expression while pRb/RBL2 represses it, thereby regulating cancer stem cell self-renewal, chemoresistance, and invasiveness through paracrine WNT signaling. The histone acetyltransferase GCN5 deposits H3K9ac on WNT promoters downstream of E2F. Quantitative proteomics of secreted proteins (CSC secretome), genetic manipulation of E2F/RB pathway, WNT expression analysis, epigenetic inhibitor screening, PDAC and breast cancer models Nature communications Medium 38678032
2008 In Dicer1-deficient mouse cells, Rbl2 protein accumulates and is responsible for decreased expression of Dnmt1, Dnmt3a, and Dnmt3b DNA methyltransferases, leading to global DNA hypomethylation and increased telomere recombination. The miR-290 cluster (downregulated in Dicer1-null cells) normally silences Rbl2 to maintain Dnmt expression. Dicer1 knockout cells, Dnmt overexpression rescue, methylation analysis, miR-290 re-expression, luciferase 3'UTR reporter assays Nature structural & molecular biology High 18311151
2022 HOXB9 transcriptionally upregulates RBL2 expression in pancreatic cancer cells. Upregulated RBL2 blocks cell cycle progression in G0/G1 and inhibits c-Myc. DNMT1 epigenetically silences HOXB9 by methylating its promoter, thus forming a DNMT1/HOXB9/RBL2/c-Myc axis regulating pancreatic cancer cell proliferation. Cell cycle PCR array, flow cytometry, ChIP-qPCR, luciferase reporter assay, xenograft and PDX mouse models, methylation analysis Cancer letters Medium 35182659
2014 TGF-β induces RBL2 expression in renal cancer cells by downregulating miR-93, which directly targets the RBL2 3'UTR. RBL2 mediates TGF-β-induced G1 growth arrest and cell cycle inhibition in these cells. qRT-PCR, Western blot, CCK-8 proliferation assay, PI staining (cell cycle), dual luciferase 3'UTR reporter assay, miR-93 overexpression/knockdown Clinical & translational oncology Medium 25183046

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Evolutionarily conserved multisubunit RBL2/p130 and E2F4 protein complex represses human cell cycle-dependent genes in quiescence. Molecular cell 341 17531812
2008 miR-17-92 cluster accelerates adipocyte differentiation by negatively regulating tumor-suppressor Rb2/p130. Proceedings of the National Academy of Sciences of the United States of America 299 18287052
2008 A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases. Nature structural & molecular biology 260 18311151
2010 Epigenetic regulation of Kaposi's sarcoma-associated herpesvirus latency by virus-encoded microRNAs that target Rta and the cellular Rbl2-DNMT pathway. Journal of virology 171 20071580
1996 Transcriptional activation of the Cu,Zn-superoxide dismutase gene through the AP2 site by ginsenoside Rb2 extracted from a medicinal plant, Panax ginseng. The Journal of biological chemistry 105 8798715
2000 Mutations in the retinoblastoma-related gene RB2/p130 in lung tumors and suppression of tumor growth in vivo by retrovirus-mediated gene transfer. Cancer research 100 10667590
2017 Ginsenoside Rb2 Alleviates Hepatic Lipid Accumulation by Restoring Autophagy via Induction of Sirt1 and Activation of AMPK. International journal of molecular sciences 95 28534819
2017 MiR-17-5p enhances pancreatic cancer proliferation by altering cell cycle profiles via disruption of RBL2/E2F4-repressing complexes. Cancer letters 80 28987387
1997 Differential expression of Rb2/p130 and p107 in normal human tissues and in primary lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 80 9815552
2014 Ginsenoside-Rb2 displays anti-osteoporosis effects through reducing oxidative damage and bone-resorbing cytokines during osteogenesis. Bone 75 24933344
2005 Transformation of ginsenosides Rb2 and Rc from Panax ginseng by food microorganisms. Biological & pharmaceutical bulletin 75 16272697
1993 The retinoblastoma-related gene, RB2, maps to human chromosome 16q12 and rat chromosome 19. Oncogene 74 8247552
1995 The RB2/p130 gene product is a nuclear protein whose phosphorylation is cell cycle regulated. Journal of cellular biochemistry 73 8567757
2000 Genetic alterations disrupting the nuclear localization of the retinoblastoma-related gene RB2/p130 in human tumor cell lines and primary tumors. Cancer research 71 10667591
2011 The antidiabetic effect of ginsenoside Rb2 via activation of AMPK. Archives of pharmacal research 70 21811928
1998 Expression of the retinoblastoma-related gene Rb2/p130 correlates with clinical outcome in endometrial cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 70 9508194
2018 Ginsenoside Rb2 inhibits epithelial-mesenchymal transition of colorectal cancer cells by suppressing TGF-β/Smad signaling. Phytomedicine : international journal of phytotherapy and phytopharmacology 63 30668333
2001 Who is the boss in the retinoblastoma family? The point of view of Rb2/p130, the little brother. Cancer research 63 11406530
2018 Ginsenoside Rb2 suppresses the glutamate-mediated oxidative stress and neuronal cell death in HT22 cells. Journal of ginseng research 62 30976171
2000 Genetic alterations of the retinoblastoma-related gene RB2/p130 identify different pathogenetic mechanisms in and among Burkitt's lymphoma subtypes. The American journal of pathology 60 10702389
2000 Mutations in the retinoblastoma-related gene RB2/p130 in primary nasopharyngeal carcinoma. Cancer research 58 10646842
2003 Purification and characterization of alpha-L-arabinopyranosidase and alpha-L-arabinofuranosidase from Bifidobacterium breve K-110, a human intestinal anaerobic bacterium metabolizing ginsenoside Rb2 and Rc. Applied and environmental microbiology 56 14660356
2002 Nucleocytoplasmic shuttling of p130/RBL2: novel regulatory mechanism. Molecular and cellular biology 55 11756542
1999 Adenoviral RB2/p130 gene transfer inhibits smooth muscle cell proliferation and prevents restenosis after angioplasty. Circulation research 54 10571534
2013 Silencing of RB1 but not of RB2/P130 induces cellular senescence and impairs the differentiation potential of human mesenchymal stem cells. Cellular and molecular life sciences : CMLS 52 23370776
2011 Bioconversion of ginsenosides Rb(1), Rb(2), Rc and Rd by novel β-glucosidase hydrolyzing outer 3-O glycoside from Sphingomonas sp. 2F2: cloning, expression, and enzyme characterization. Journal of biotechnology 51 21906640
2009 Rb2/p130 is the dominating pocket protein in the p53-p21 DNA damage response pathway leading to senescence. Oncogene 49 19648966
2004 Glycogen synthase kinase 3 phosphorylates RBL2/p130 during quiescence. Molecular and cellular biology 48 15456871
2018 Ginsenoside Rb2 promotes glucose metabolism and attenuates fat accumulation via AKT-dependent mechanisms. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 46 29425748
1996 Genomic structure of the human retinoblastoma-related Rb2/p130 gene. Proceedings of the National Academy of Sciences of the United States of America 46 8643454
2016 Ginsenoside Rb2 enhances the anti-inflammatory effect of ω-3 fatty acid in LPS-stimulated RAW264.7 macrophages by upregulating GPR120 expression. Acta pharmacologica Sinica 45 28017961
2020 Ginsenoside Rb2 alleviates myocardial ischemia/reperfusion injury in rats through SIRT1 activation. Journal of food science 43 33073372
2020 Ginsenoside Rb2 improves insulin resistance by inhibiting adipocyte pyroptosis. Adipocyte 41 32580621
2002 Expression of RB2/p130 tumor-suppressor gene in AIDS-related non-Hodgkin's lymphomas: implications for disease pathogenesis. Human pathology 41 12196924
2022 HOXB9 blocks cell cycle progression to inhibit pancreatic cancer cell proliferation through the DNMT1/RBL2/c-Myc axis. Cancer letters 40 35182659
2001 RB2/p130 gene-enhanced expression down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in vivo. Cancer research 40 11212232
2019 Ginsenoside Rb2 Alleviates Obesity by Activation of Brown Fat and Induction of Browning of White Fat. Frontiers in endocrinology 39 30930854
2014 Ginsenoside-Rb2 inhibits dexamethasone-induced apoptosis through promotion of GPR120 induction in bone marrow-derived mesenchymal stem cells. Stem cells and development 39 25314926
2002 The cancer preventive flavonoid silibinin causes hypophosphorylation of Rb/p107 and Rb2/p130 via modulation of cell cycle regulators in human prostate carcinoma DU145 cells. Cell cycle (Georgetown, Tex.) 39 12429923
2010 Transient arrest in a quiescent state allows ovarian cancer cells to survive suboptimal growth conditions and is mediated by both Mirk/dyrk1b and p130/RB2. International journal of cancer 38 20857490
2019 Ginsenoside Rb1 and Rb2 upregulate Akt/mTOR signaling-mediated muscular hypertrophy and myoblast differentiation. Journal of ginseng research 37 32372865
2006 Cooperation between p53 and p130(Rb2) in induction of cellular senescence. Cell death and differentiation 37 16123778
2003 Protein phosphatase 2A associates with Rb2/p130 and mediates retinoic acid-induced growth suppression of ovarian carcinoma cells. The Journal of biological chemistry 37 12915404
2009 Senescence and p130/Rbl2: a new beginning to the end. Cell research 36 19668264
2001 Inhibitory effect of ginsenoside-Rb2 on invasiveness of uterine endometrial cancer cells to the basement membrane. European journal of gynaecological oncology 36 11766734
2009 The ginsenoside-Rb2 lowers cholesterol and triacylglycerol levels in 3T3-L1 adipocytes cultured under high cholesterol or fatty acids conditions. BMB reports 35 19403041
2001 Expression of the retinoblastoma-related gene Rb2/p130 is downregulated in atypical endometrial hyperplasia and adenocarcinoma. Human pathology 34 11331952
2020 Ginsenoside Rb2 Ameliorates LPS-Induced Inflammation and ER Stress in HUVECs and THP-1 Cells via the AMPK-Mediated Pathway. The American journal of Chinese medicine 33 32431178
1998 Repetitive sequences (RPSs) in the chromosomes of Candida albicans are sandwiched between two novel stretches, HOK and RB2, common to each chromosome. Microbiology (Reading, England) 32 9579060
2017 Downregulation of PARP1 transcription by promoter-associated E2F4-RBL2-HDAC1-BRM complex contributes to repression of pluripotency stem cell factors in human monocytes. Scientific reports 31 28842672
2002 Epidermis proliferative effect of the Panax ginseng ginsenoside Rb2. Archives of pharmacal research 31 11885696
2012 Enzymatic transformation of the major ginsenoside Rb2 to minor compound Y and compound K by a ginsenoside-hydrolyzing β-glycosidase from Microbacterium esteraromaticum. Journal of industrial microbiology & biotechnology 30 22717707
2001 Interplay between the antimetastatic nm23 and the retinoblastoma-related Rb2/p130 genes in promoting neuronal differentiation of PC12 cells. Cell death and differentiation 30 11423907
2019 Combination of the ginsenosides Rb3 and Rb2 exerts protective effects against myocardial ischemia reperfusion injury in rats. International journal of molecular medicine 29 31789417
2011 Mature mice lacking Rbl2/p130 gene have supernumerary inner ear hair cells and supporting cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 29 21677172
2005 Genetic and epigenetic alterations of RB2/p130 tumor suppressor gene in human sporadic retinoblastoma: implications for pathogenesis and therapeutic approach. Oncogene 29 16007224
2020 FGFR1 Is Critical for RBL2 Loss-Driven Tumor Development and Requires PLCG1 Activation for Continued Growth of Small Cell Lung Cancer. Cancer research 28 32973083
2018 RBL2/p130 is a direct AKT target and is required to induce apoptosis upon AKT inhibition in lung cancer and mesothelioma cell lines. Oncogene 28 29606701
2018 The anti-metastatic effect of ginsenoside Rb2 in colorectal cancer in an EGFR/SOX2-dependent manner. Cancer medicine 28 30264477
2010 The tumor suppressor Rb and its related Rbl2 genes are regulated by Utx histone demethylase. Biochemical and biophysical research communications 28 20650264
2000 A CDE/CHR-like element mediates repression of transcription of the mouse RB2 (p130) gene. FEBS letters 28 10760507
2017 Highly regioselective biotransformation of ginsenoside Rb2 into compound Y and compound K by β-glycosidase purified from Armillaria mellea mycelia. Journal of ginseng research 27 30337811
2007 Gene-expression analysis identifies novel RBL2/p130 target genes in endemic Burkitt lymphoma cell lines and primary tumors. Blood 27 17485552
1998 The RB-related gene Rb2/p130 in neuroblastoma differentiation and in B-myb promoter down-regulation. Cell death and differentiation 27 10200489
2022 Immunomodulatory Effect of Ginsenoside Rb2 Against Cyclophosphamide-Induced Immunosuppression in Mice. Frontiers in pharmacology 26 35814238
2021 Inhibitory role of ginsenoside Rb2 in endothelial senescence and inflammation mediated by microRNA‑216a. Molecular medicine reports 26 33786633
2006 Regulation of cellular senescence by Rb2/p130. Oncogene 26 16936745
2023 Ginsenoside Rb2 inhibits p300-mediated SF3A2 acetylation at lysine 10 to promote Fscn1 alternative splicing against myocardial ischemic/reperfusion injury. Journal of advanced research 25 38101749
2001 Expression of Rb2/p130 in breast and endometrial cancer: correlations with hormone receptor status. British journal of cancer 25 11506494
1995 Molecular cloning, expression, and developmental characterization of the murine retinoblastoma-related gene Rb2/p130. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 25 9019172
2011 CTCF and BORIS regulate Rb2/p130 gene transcription: a novel mechanism and a new paradigm for understanding the biology of lung cancer. Molecular cancer research : MCR 24 21325284
2006 Rb2/p130 and protein phosphatase 2A: key mediators of ovarian carcinoma cell growth suppression by all-trans retinoic acid. Oncogene 24 16936753
2005 RB and RB2/p130 genes demonstrate both specific and overlapping functions during the early steps of in vitro neural differentiation of marrow stromal stem cells. Cell death and differentiation 24 15459751
2014 Korean red ginseng saponin fraction rich in ginsenoside-Rb1, Rc and Rb2 attenuates the severity of mouse collagen-induced arthritis. Mediators of inflammation 23 24833816
2013 Isolation and characterization of novel ginsenoside-hydrolyzing glycosidase from Microbacterium esteraromaticum that transforms ginsenoside Rb2 to rare ginsenoside 20(S)-Rg3. Antonie van Leeuwenhoek 23 23670791
2018 MiRNA-93 functions as an oncogene in glioma by directly targeting RBL2. European review for medical and pharmacological sciences 22 29762838
2015 Melanin Biosynthesis Inhibition Effects of Ginsenoside Rb2 Isolated from Panax ginseng Berry. Journal of microbiology and biotechnology 22 26437949
2012 The switch from pRb/p105 to Rb2/p130 in DNA damage and cellular senescence. Journal of cellular physiology 22 21465484
2022 Ginsenoside Rb2 Alleviated Atherosclerosis by Inhibiting M1 Macrophages Polarization Induced by MicroRNA-216a. Frontiers in pharmacology 21 35046806
2017 Ginsenoside Rb2 inhibits osteoclast differentiation through nuclear factor-kappaB and signal transducer and activator of transcription protein 3 signaling pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 21 28605877
2013 Silencing of RB1 and RB2/P130 during adipogenesis of bone marrow stromal cells results in dysregulated differentiation. Cell cycle (Georgetown, Tex.) 21 24281253
2006 Interaction of PP2A catalytic subunit with Rb2/p130 is required for all-trans retinoic acid suppression of ovarian carcinoma cell growth. Journal of cellular physiology 21 16206244
2024 The pRb/RBL2-E2F1/4-GCN5 axis regulates cancer stem cell formation and G0 phase entry/exit by paracrine mechanisms. Nature communications 20 38678032
2021 Cyclin F drives proliferation through SCF-dependent degradation of the retinoblastoma-like tumor suppressor p130/RBL2. eLife 19 34851822
2004 Role of RB and RB2/P130 genes in marrow stromal stem cells plasticity. Journal of cellular physiology 19 15174090
2000 The RB2/p130 gene: the latest weapon in the war against lung cancer? Clinical cancer research : an official journal of the American Association for Cancer Research 19 10741694
2022 Ginsenoside Rb2 suppresses cellular senescence of human dermal fibroblasts by inducing autophagy. Journal of ginseng research 17 36926607
1998 Molecular cloning, expression, and enzymatic characterization of rabbit hydroxysteroid sulfotransferase AST-RB2. Journal of biochemistry 17 9538269
2023 Efficient Suppression of Dendrites and Side Reactions by Strong Electrostatic Shielding Effect via the Additive of Rb2 SO4 for Anodes in Aqueous Zinc-Ion Batteries. Small (Weinheim an der Bergstrasse, Germany) 16 37649229
2023 Ginsenoside Rb2 improves heart failure by down-regulating miR-216a-5p to promote autophagy and inhibit apoptosis and oxidative stress. Journal of applied biomedicine 16 38112457
2014 TGF-beta induced RBL2 expression in renal cancer cells by down-regulating miR-93. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 16 25183046
2022 RBL2/DREAM-mediated repression of the Aurora kinase A/B pathway determines therapy responsiveness and outcome in p53 WT NSCLC. Scientific reports 15 35058503
2015 Ginsenoside Rb2 Attenuates UV-B Radiation-Induced Reactive Oxygen Species and Matrix Metalloproteinase-2 through Upregulation of Antioxidant Components in Human Dermal Fibroblasts. Pharmacology 15 26043782
2009 High incidence of allelic loss at 16q12.2 region spanning RBL2/p130 gene in retinoblastoma. Cancer biology & therapy 15 19252413
2006 Cell cycle regulators p105, p107, Rb2/p130, E2F4, p21CIP1/WAF1, cyclin A in predicting cervical intraepithelial neoplasia, high-risk human papillomavirus infections and their outcome in women screened in three new independent states of the former Soviet Union. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 15 16835319
2005 Tumor-specific exon 1 mutations could be the 'hit event' predisposing Rb2/p130 gene to epigenetic silencing in lung cancer. Oncogene 15 16044156
2001 The retinoblastoma-related Rb2/p130 gene is an effector downstream of AP-2 during neural differentiation. Oncogene 15 11420667
1995 [Calcium channel blockade and anti-free-radical actions of panaxadiol saponins Rb1, Rb2, Rb3, Rc, and Rd]. Zhongguo yao li xue bao = Acta pharmacologica Sinica 15 7660823
2022 Effect of Ginsenoside Rb2 on a Myocardial Cell Model of Coronary Heart Disease through Nrf2/HO-1 Signaling Pathway. Biological & pharmaceutical bulletin 14 34980781
2021 Combination of Ginsenosides Rb2 and Rg3 Promotes Angiogenic Phenotype of Human Endothelial Cells via PI3K/Akt and MAPK/ERK Pathways. Frontiers in pharmacology 14 33643049

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