Affinage

RB1

Retinoblastoma-associated protein · UniProt P06400

Round 2 corrected
Length
928 aa
Mass
106.2 kDa
Annotated
2026-04-28
130 papers in source corpus 50 papers cited in narrative 45 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RB1 encodes a nuclear phosphoprotein that functions as a master tumor suppressor governing cell cycle progression, differentiation, senescence, and genome stability. Hypophosphorylated pRb binds E2F transcription factors via its A/B pocket domain and recruits chromatin-modifying complexes—including HDAC1, SUV39H1–HP1, DNMT1, EZH2/Polycomb group proteins, and PRMT2—to repress S-phase gene promoters and silence repetitive genomic elements (PMID:9468139, PMID:11484059, PMID:10888886, PMID:27889452, PMID:16616919). Sequential CDK4/6-then-CDK2 phosphorylation progressively inactivates pRb—first displacing HDAC by C-terminal phosphorylation (notably T373) while pRb remains chromatin-bound, then disrupting the pocket to release E2F—while PP1 dephosphorylates pRb at mitotic exit to restore its repressive state (PMID:10499802, PMID:38926571, PMID:8384581). Beyond cell cycle control, pRb makes genetically separable contributions to lineage determination by interacting with tissue-specific transcription factors such as MyoD (myogenesis), Runx2 (osteogenesis), and ZEB1 (EMT suppression), and its biallelic inactivation causes retinoblastoma and predisposes to osteosarcoma (PMID:8381715, PMID:20686481, PMID:16449662, PMID:3823889).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1987 High

    Establishing that RB1 encodes a tangible product—a nuclear phosphoprotein with DNA-binding capacity—whose loss defines retinoblastoma, transforming the locus from a genetic concept to a biochemically tractable molecule.

    Evidence Immunoprecipitation, metabolic labeling, immunofluorescence, and cDNA cloning in retinoblastoma cell lines and normal cells

    PMID:3657987 PMID:3823889

    Open questions at the time
    • No interacting partners identified
    • Function beyond DNA binding unknown
    • Phosphorylation significance unclear
  2. 1988 High

    Demonstrating that DNA tumor virus oncoproteins (SV40 T antigen, adenovirus E1A, HPV E7) physically sequester pRb via an LXCXE motif established pRb inactivation as the common mechanism of viral transformation and implied pRb normally restrains proliferation.

    Evidence Reciprocal co-immunoprecipitation with transformation-defective T antigen mutants; HPV E7 binding studies across high- and low-risk types with domain mapping

    PMID:2537532 PMID:2556261 PMID:2839300

    Open questions at the time
    • Cellular target of pRb growth suppression unknown
    • Pocket domain not yet structurally defined
  3. 1992 High

    Identification of E2F as the critical cellular binding partner of pRb, and demonstration that Rb-null mice die mid-gestation with neurogenesis and erythropoiesis defects, established that pRb represses E2F-driven transcription and is essential for development.

    Evidence Two-hybrid screen identifying RBP3/E2F, EMSA and reporter assays; Rb1 homozygous knockout mice with transgene rescue

    PMID:1406932 PMID:1406933 PMID:1638634

    Open questions at the time
    • How pRb represses transcription mechanistically (chromatin remodeling?) unknown
    • Cell-type-specific requirements unresolved
  4. 1993 High

    Discovery that cyclin D–CDK4 complexes directly phosphorylate pRb and that PP1 dephosphorylates it at mitotic exit defined the enzymes that toggle pRb between active and inactive states, linking the CDK-Rb-E2F axis as the core G1/S regulatory module.

    Evidence Baculovirus reconstitution of cyclin D–CDK4 kinase activity on pRb; yeast two-hybrid and in vitro binding of PP1α to hypophosphorylated pRb with cell cycle timing

    PMID:8384581 PMID:8449399 PMID:8490963

    Open questions at the time
    • Whether CDK4 and CDK2 phosphorylate distinct sites is unclear
    • Order of phosphorylation events unresolved
  5. 1993 High

    Demonstrating that pRb directly binds MyoD through its pocket domain and that Rb inactivation prevents terminal muscle differentiation revealed a differentiation-promoting function genetically separable from proliferation control.

    Evidence In vivo and in vitro co-immunoprecipitation; Rb-null cells fail to maintain post-mitotic muscle state

    PMID:8381715

    Open questions at the time
    • Whether Rb-MyoD interaction requires E2F displacement unclear
    • How pRb pocket accommodates both E2F and MyoD unresolved
  6. 1998 High

    Discovery that pRb recruits HDAC1 to E2F-regulated promoters established that pRb is not merely a passive E2F shield but an active transcriptional repressor that remodels chromatin; concurrently, Ras-induced senescence was shown to require p16–Rb pathway integrity.

    Evidence Co-immunoprecipitation of pRb–HDAC1, TSA-sensitive repression of integrated cyclin E reporter; retroviral Ras expression in primary cells with p16/p53 genetic inactivation

    PMID:9054499 PMID:9468139 PMID:9468140

    Open questions at the time
    • Other chromatin-modifying partners not yet identified
    • Whether HDAC recruitment is sufficient for stable silencing unknown
  7. 1999 High

    Reconstitution of sequential phosphorylation resolved how CDK4/6 first phosphorylates C-terminal sites to displace HDAC (ending active repression) while CDK2 subsequently phosphorylates pocket residues to release E2F, explaining how two kinase waves progressively dismantle pRb function through G1.

    Evidence In vitro sequential kinase assays, intramolecular interaction mapping, CDK inhibitor treatment, co-immunoprecipitation

    PMID:10499802

    Open questions at the time
    • In vivo single-cell dynamics of sequential phosphorylation unknown
    • Which specific sites CDK4/6 vs CDK2 prefer in living cells unclear
  8. 2001 High

    Demonstrating that pRb recruits SUV39H1–HP1 and Polycomb group complexes to target promoters extended pRb's repressive toolkit beyond HDAC to include histone methylation and heterochromatic silencing, providing a mechanism for stable, heritable gene repression.

    Evidence Co-IP of pRb with SUV39H1 and HP1; ChIP showing Rb-dependent H3K9me and HP1 at cyclin E promoter; co-IP and colocalization of Rb with PcG bodies

    PMID:11484059 PMID:11583618

    Open questions at the time
    • How pRb coordinates multiple chromatin complexes at a single promoter unresolved
    • Temporal order of HDAC vs HMT recruitment unknown
  9. 2003 High

    Linking pRb to senescence-associated heterochromatic foci (SAHF) formation showed that pRb-mediated chromatin compaction enforces irreversible cell cycle exit during oncogene-induced senescence, distinguishing permanent from reversible arrest.

    Evidence ChIP of Rb at E2F promoters during SAHF formation; Rb pathway disruption prevents SAHF; BrdU incorporation in senescent cells

    PMID:12809602

    Open questions at the time
    • Structural basis of SAHF and Rb's precise architectural role unclear
    • Whether all senescence programs require SAHF is unresolved
  10. 2006 High

    An E2F-binding-deficient Rb1 knock-in mouse (R654W) separated cell cycle control from differentiation: embryos phenocopied null cell cycle defects but showed improved erythrocyte and macrophage differentiation, proving pRb makes genetically distinct contributions to lineage commitment.

    Evidence Knock-in R654W point mutant mouse with survival analysis and differentiation assays

    PMID:16449662

    Open questions at the time
    • Identity of the non-E2F partners mediating differentiation only partially known (Runx2, PPARγ identified)
    • Structural basis of pocket's dual specificity unresolved
  11. 2010 High

    Conditional Rb deletion in mesenchymal precursors shifted lineage fate from bone to brown fat in vivo, confirming that Rb governs mesenchymal stem cell commitment and linking this function to osteosarcoma pathogenesis.

    Evidence Tissue-specific conditional knockout mice with histological lineage analysis

    PMID:20686481

    Open questions at the time
    • Direct molecular targets mediating lineage switch beyond PPARγ/Runx2 incompletely defined
    • Whether Rb's chromatin remodeling vs E2F functions drive lineage choice unclear
  12. 2012 High

    SMYD2-mediated methylation of pRb at Lys810 was shown to enhance Ser807/811 phosphorylation and accelerate G1/S transition, revealing a post-translational crosstalk layer that tunes CDK-mediated Rb inactivation.

    Evidence In vitro methyltransferase assay, LC-MS/MS site identification, SMYD2 knockdown cell cycle analysis

    PMID:22787429

    Open questions at the time
    • Whether Lys810 methylation occurs on chromatin-bound Rb unknown
    • Demethylase that reverses this mark not identified
  13. 2016 High

    An Rb1 F832A knock-in mouse revealed that pRb uses a cell-cycle-independent interaction with E2F1 to recruit EZH2 and deposit H3K27me3 at repetitive genomic elements; loss of this function derepresses repeats and increases lymphoma susceptibility, establishing a genome-stability role distinct from canonical cell cycle control.

    Evidence ChIP-seq for Rb and H3K27me3 in F832A knock-in; repeat expression analysis; tumor incidence in aging mice

    PMID:27889452

    Open questions at the time
    • Whether repeat derepression directly causes chromosomal instability or acts through transposon mobilization unclear
    • Full repertoire of Rb-silenced repeats not catalogued
  14. 2018 High

    Single-cell imaging revealed that daughter cells bifurcate within minutes of mitosis based on Rb phosphorylation state, with T373 phosphorylated preferentially first due to slow dephosphorylation, and p21 levels in G2 predict the post-mitotic fate, providing quantitative in vivo resolution of the restriction-point decision.

    Evidence Live single-cell E2F/CDK2 reporters, phospho-specific western blot, flow cytometry

    PMID:30111539

    Open questions at the time
    • Phosphatase identity responsible for rapid dephosphorylation of non-T373 sites unresolved
    • How chromatin context modulates the bifurcation threshold unknown
  15. 2024 High

    Identification of a reversible 'primed' intermediate state—where mono-phosphorylated (T373) Rb remains chromatin-bound and partially active—resolved how cells can sample commitment to proliferation without irrevocably crossing the restriction point, until full multi-site hyperphosphorylation triggers positive feedback and E2F activation.

    Evidence Single-cell E2F/CDK2 reporters, phospho-specific antibodies, chromatin fractionation, CDK inhibitor dose-response

    PMID:38926571

    Open questions at the time
    • Whether the primed state has distinct transcriptional outputs (partial E2F target activation) unknown
    • Structural basis of how T373 phosphorylation alters pocket conformation without disrupting E2F binding unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How pRb coordinates its multiple chromatin-remodeling activities (HDAC, SUV39H1–HP1, EZH2–PcG, DNMT1) at individual loci in a context- and cell-type-dependent manner, and how the primed mono-phosphorylated intermediate integrates with lineage-specific differentiation programs, remain major open questions.
  • No time-resolved chromatin occupancy data linking sequential Rb phosphoforms to specific corepressor swaps at single loci
  • Structural basis of pocket domain accommodating diverse LXCXE and non-LXCXE partners simultaneously unresolved
  • Whether Rb's repeat-silencing function is mechanistically linked to its differentiation role is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0098772 molecular function regulator activity 4 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 5 GO:0005654 nucleoplasm 3 GO:0005694 chromosome 2
Pathway
R-HSA-1640170 Cell Cycle 7 R-HSA-1643685 Disease 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1266738 Developmental Biology 4 R-HSA-4839726 Chromatin organization 4 R-HSA-5357801 Programmed Cell Death 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
DNMT1E2F1EZH2HDAC1MYOD1PP1SMYD2SUV39H1
Complex memberships
pRb–E2F repressor complexpRb–EZH2/Polycomb complexpRb–HDAC1 corepressor complexpRb–SUV39H1–HP1 complex

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1987 The RB1 gene encodes a nuclear phosphoprotein of 110-114 kDa with DNA-binding activity, expressed in normal cells but absent in retinoblastoma cell lines. Immunoprecipitation, metabolic 32P-labeling, biochemical fractionation, immunofluorescence, DNA-cellulose binding assay Nature High 3657987
1987 The RB1 gene encodes a predicted 816-amino acid protein with potential metal-binding/nucleic acid-binding domains; homozygous deletions and abnormal transcripts occur in retinoblastomas. cDNA cloning, sequencing, Southern blot, Northern blot Science High 3823889
1988 SV40 large T antigen forms a specific complex with the RB1 gene product (p110-114); T antigen mutants altered in a transformation-controlling domain fail to complex with pRb, linking pRb binding to transformation. Co-immunoprecipitation, deletion mutagenesis of T antigen Cell High 2839300
1989 HPV-16 E7 oncoprotein binds the RB1 gene product (p105-RB) in a manner similar to adenovirus E1A and SV40 T antigen, implicating RB binding in HPV-associated carcinogenesis. Co-immunoprecipitation mixing assays in vitro and in vivo Science High 2537532
1989 HPV E7 proteins (types 16, 18, 6b, 11) form complexes with p105-RB; high-risk HPV types (16, 18) bind with higher affinity than low-risk types (6b, 11); the LXCXE-related N-terminal domain mediates binding. Co-immunoprecipitation, domain mapping, in vitro binding assays The EMBO journal High 2556261
1989 RB1 mutations in retinoblastoma tumors include small deletions, duplications, and splice-altering point mutations; expression of mutant alleles is suppressed in the presence of a functional RB1 gene product, suggesting transcriptional autoregulation. PCR, RNase protection assay, sequence analysis Molecular and cellular biology Medium 2601691
1992 E2F encodes (or an E2F-like protein, RBP3) a transcription factor that binds pRb both in vitro and in vivo; this binding is competed by viral oncoproteins that disrupt pRb-E2F association; RBP3 transactivates the adenovirus E2 promoter via E2F sites. Two-hybrid screen, co-immunoprecipitation, EMSA, transient transfection reporter assay Cell High 1638634
1992 Rb1 homozygous knockout mice die by embryonic day 14-16 with defects in neurogenesis (ectopic mitoses, massive cell death in hindbrain, spinal ganglion cell death) and haematopoiesis (increase in immature nucleated erythrocytes); a human RB mini-transgene rescues these defects. Gene targeting (insertional mutation), mouse knockout, transgene rescue Nature High 1406932 1406933 1406937
1993 Protein phosphatase type 1 catalytic subunit (PP-1α) associates with pRb; PP-1α isoforms preferentially bind the hypophosphorylated form of pRb; this association occurs from mitosis to early G1, suggesting PP-1 dephosphorylates pRb at mitotic exit. Yeast two-hybrid, in vitro binding assays, cell cycle synchrony experiments Genes & development High 8384581
1993 Cyclin D1 and D3 physically bind pRb directly, forming complexes resembling those of viral oncoproteins; a conserved LXCXE-like motif in D cyclins mediates pRb binding; mutation of this motif prevents complex formation and enhances cyclin D1 biological activity. Co-immunoprecipitation in insect Sf9 cells, baculovirus co-expression, mutagenesis Cell High 8490963
1993 Cyclin D-CDK4 complexes phosphorylate pRb in vitro and in vivo at sites identical to those phosphorylated in human T cells; CDK4+cyclin D2/D3 complexes induce pRb hyperphosphorylation and dissociation from E2F-1 in insect cells. Baculovirus co-expression in Sf9 cells, in vitro kinase assay, co-immunoprecipitation, kinase-dead CDK4 mutant Genes & development High 8449399
1993 pRb directly binds MyoD both in vivo and in vitro through the pRb pocket domain and the MyoD basic-HLH domain; pRb inactivation (by phosphorylation, T antigen binding, or genetic deletion) inhibits myogenesis and allows terminally differentiated muscle cells to re-enter the cell cycle. Co-immunoprecipitation in vivo and in vitro, genetic inactivation of pRb, cell differentiation assays Cell High 8381715
1997 CDK-mediated phosphorylation of RB inhibits E2F binding through two distinct mechanisms: (i) phosphorylation of C-terminal sites directly inhibits E2F binding; (ii) phosphorylation of insert-domain serines inhibits E2F binding in an N-terminal-region-dependent manner. LXCXE binding is inactivated by Thr821/Thr826 phosphorylation; c-Abl (C pocket) binding by Ser807/Ser811 phosphorylation. Site-directed mutagenesis of phosphorylation sites, in vitro binding assays, cell-based G1 arrest assays Molecular and cellular biology High 9315635
1998 pRb recruits histone deacetylase HDAC1 through its pocket domain to repress E2F-regulated promoters (e.g., cyclin E); naturally occurring pocket mutations and HPV E7 reduce HDAC1 association; HDAC inhibitor TSA blocks Rb-mediated repression of a chromosomally integrated E2F promoter. Co-immunoprecipitation, reporter assay, TSA inhibition of integrated promoter Nature High 9468139 9468140 9491888
1998 During apoptosis, hyperphosphorylated RB is converted to a hypophosphorylated form by a serine/threonine phosphatase, and subsequently cleaved by caspase-family proteases; caspase-3-like activity cleaves the RB C-terminus; unphosphorylated RB functions as an inhibitor of apoptosis. In vitro apoptosis assays, protease inhibitor studies, biochemical fractionation Frontiers in bioscience Medium 9545437 9695821
1998 The RB C pocket (distinct from the A/B pocket and E2F-binding activity) contributes to growth suppression; C-pocket mutations combined with E2F/LXCXE-binding-deficient mutation 661 completely abolish G1 arrest and terminal growth arrest, showing the C pocket provides an independent growth-suppressive mechanism. Site-directed mutagenesis, cell-based G1 arrest and terminal growth arrest assays Molecular and cellular biology High 9632788
1999 CDK4/6 phosphorylates the RB C-terminal region first, displacing HDAC from the pocket and blocking active transcriptional repression; subsequently CDK2 phosphorylates the pocket itself, disrupting pocket structure and preventing E2F binding, providing a molecular basis for sequential Rb inactivation through G1. In vitro phosphorylation, intramolecular interaction assays, CDK inhibition, co-immunoprecipitation Cell High 10499802
1999 Rb and p27 operate on overlapping but distinct tumor-suppressive pathways; Rb+/−p27−/− double-mutant mice develop pituitary adenocarcinoma with accelerated kinetics and high-grade thyroid C cell carcinoma more aggressive than in either single mutant, demonstrating genetic cooperation between Rb and CDK inhibitor p27. Mouse genetics, compound mutant analysis, tumor histology PNAS High 10339596
2000 DNMT1 co-purifies with Rb, E2F1, and HDAC1 and cooperates with Rb to repress transcription from E2F-binding-site-containing promoters, establishing a link between DNA methylation and pRb-mediated transcriptional silencing. Co-purification, co-immunoprecipitation, reporter transcription assay Nature genetics High 10888886
2000 EID-1, a novel Rb-binding protein with an LXCXE motif, binds both Rb (via A-B pocket) and p300 (inhibiting its histone acetyltransferase activity); EID-1 represses MyoD-dependent muscle-specific transcription independent of G1 exit by blocking p300 coactivator function. Yeast two-hybrid, co-immunoprecipitation, histone acetyltransferase assay, transcription reporter assay, overexpression Molecular and cellular biology High 11073990
2001 Rb associates with SUV39H1 (histone H3 Lys9 methyltransferase) and HP1 via its pocket domain in vivo; SUV39H1 cooperates with Rb to repress the cyclin E promoter; ChIP shows Rb is required for H3K9 methylation and HP1 recruitment to the cyclin E promoter, linking Rb to heterochromatic gene silencing. Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), reporter assay, SUV39H fibroblast knockouts Nature High 11484059
2001 Rb associates with Polycomb group (PcG) proteins and colocalizes with nuclear PcG complexes; Rb-PcG complexes repress entry into mitosis and Rb is required for association of PcG complexes with nuclear targets, linking cell cycle arrest to Polycomb-mediated developmental gene regulation. Co-immunoprecipitation, immunofluorescence colocalization, functional cell cycle assays Molecular cell Medium 11583618
2003 During oncogene-induced senescence, Rb is recruited to E2F-responsive promoters coincident with formation of senescence-associated heterochromatic foci (SAHF); SAHF formation and stable repression of E2F target genes depend on intact Rb pathway function and do not occur in reversibly arrested cells. ChIP, immunofluorescence, Rb pathway genetic disruption, bromodeoxyuridine incorporation Cell High 12809602
2006 PRMT2 (arginine methyltransferase) directly binds Rb through its AdoMet binding domain (distinct from other PRMT family members) and forms a ternary complex with E2F1 and Rb to repress E2F1 transcriptional activity in an Rb-dependent manner; PRMT2−/− MEFs show increased E2F activity and early S phase entry. Co-immunoprecipitation, reporter assay, gene targeting (PRMT2 knockout), cell cycle analysis Experimental cell research High 16616919
2006 pRb binds Runx2 and potentiates osteogenic differentiation; pRb also acts with E2F to suppress PPARγ (master adipogenesis activator), indicating pRb plays a context-dependent role in promoting or suppressing transcription factor activity to regulate lineage choice. Reviewed mechanistic studies; in vitro binding assays and transcription reporter assays cited Oncogene Medium 16936739
2010 Rb loss in vivo drives fate choice between bone and brown adipose tissue in mesenchymal tissue; Rb status determines commitment to osteogenic vs. adipogenic lineage in mouse mesenchymal stem cells and is linked to osteosarcoma development. Conditional mouse knockout models (tissue-specific Rb deletion), histology, lineage tracing Nature High 20686481
2010 RB-E2F pathway directly regulates neogenin expression: Rb represses E2F-mediated neogenin transcription; E2F3 occupies E2F consensus sites on the neogenin promoter in native chromatin; Rb loss leads to aberrant neuronal migration via neogenin-netrin-1 signaling. ChIP, promoter reporter assay, ex vivo electroporation, neuronal migration assay, Rb conditional knockout Molecular and cellular biology High 21059867
2010 RB induces autophagy by repressing E2F1 activity; RB binding to E2F is required for autophagy induction; E2F1 antagonizes RB-induced autophagy leading to apoptosis; CDK inhibitors p16INK4a and p27/kip1 induce autophagy in an RB-dependent manner. RB overexpression/knockdown, E2F1 knockdown, autophagy assays (GFP-LC3), genetic epistasis Cancer research Medium 20807803
2010 RB family members (Rb, p107, p130) and E2F family members bind directly to the Rb promoter and modulate its transcription in specific cell populations in vivo, establishing a regulatory feedback loop within the RB pathway. ChIP, reporter transgenic mice (BAC-eGFP), genetic crosses with Rb/p107/p130 mutant alleles Molecular and cellular biology High 20100864
2010 NORE1A connects Ras to Rb activation: Ras induces formation of a NORE1A-PP1A phosphatase complex that dephosphorylates Rb, activating the tumor suppressor; suppression of Rb reduces NORE1A-induced senescence. Co-immunoprecipitation, phosphatase assay, senescence assays, knockdown Journal of Biological Chemistry Medium 26677227
2012 SMYD2 methyltransferase methylates RB1 protein at Lys810 in vitro and in vivo; this methylation enhances Ser807/811 phosphorylation of RB1, accelerates E2F transcriptional activity, and promotes cell cycle progression (G1/S transition). In vitro methyltransferase assay, LC-MS/MS identification of methylation site, cell cycle analysis, SMYD2 knockdown Neoplasia High 22787429
2012 Active RB/E2F complexes repress the miR-106b cluster (intragenic in MCM7) in a CDK4/6-inhibition-dependent, E2F- and RB-dependent manner; RB-mediated repression of the 106b cluster elevates p21Cip1 and PTEN transcript levels. miRNA expression profiling, CDK4/6 inhibitor treatment, ChIP, RB/E2F knockdown Cell cycle Medium 23255112
2013 RB1 controls fate determination in spermatogonial stem cells (SSCs): conditional Rb1 inactivation in prospermatogonial precursors impairs SSC renewal leading to progressive germline loss; Rb1 inactivation in progenitor spermatogonia causes some cells to acquire tumorigenic properties (carcinoma in situ-like state, invasiveness after transplant). Conditional knockout mice, spermatogonial transplantation assay, Rb1 knockdown in primary cultures Biology of reproduction Medium 24089198
2014 Loss of Rb promotes ferroptosis (oxidative necrosis) in response to sorafenib in hepatocellular carcinoma cells; Rb-negative HCC cells exhibit 2-3-fold increased cell death and complete tumor regression in xenograft models. Stable RNAi knockdown of Rb, cell death assays, xenograft mouse model, ferroptosis characterization Cancer letters Medium 25444922
2014 In Rb1-deficient pituitary tumorigenesis, Skp2 suppresses apoptosis by limiting E2F1 activity through a pRb-Skp2-p27-cyclin A-E2F1 pathway: Skp2 deletion stabilizes p27, which prevents cyclin A from binding and inhibiting E2F1 at target promoters, converting E2F1 from a proliferative to apoptotic factor. Mouse genetics (Rb1/Skp2/p27 compound mutants), ChIP, co-immunoprecipitation, pituitary tumor analysis Nature communications High 24632684
2016 pRb utilizes a cell-cycle-independent interaction with E2F1 to recruit EZH2 to diverse repetitive genomic sequences (simple repeats, satellites, LINEs, endogenous retroviruses); an F832A point mutation in Rb1 disrupts this recruitment, dispersing H3K27me3 from repeat sequences and permitting repeat expression, with increased lymphoma susceptibility. ChIP-seq, mutant knock-in mouse (Rb1 F832A), ChIP for H3K27me3, repeat expression analysis Molecular cell High 27889452
2016 Dephosphorylated Rb associates with ZEB1 (zinc-finger E-box binding transcription factor) and inhibits ZEB1 transcriptional activity, thereby suppressing epithelial-to-mesenchymal transition (EMT); induction of Rb dephosphorylation (via PNUTS/PP1 axis) reduces invasiveness in mesenchymal cancer cells. PNUTS shRNA-mediated PP1 activation, 3D Matrigel culture, co-immunoprecipitation (Rb-ZEB1), ZEB1 reporter assay, invasion assay Cancer biology & therapy Medium 27645778
2018 Aspartate beta-hydroxylase (ASPH) promotes RB1 phosphorylation by facilitating direct protein interactions between RB1, CDKs, and cyclins; ASPH knockdown reduces CDK4-RB1 interaction and RB1 phosphorylation, inhibiting cholangiocarcinoma progression. Co-immunoprecipitation, xenograft model, ASPH knockdown, 2-OG dioxygenase inhibitors Cancer letters Medium 29733964
2018 Cells bifurcate after anaphase into two subpopulations defined by Rb phosphorylation state within minutes: one with hyperphosphorylated Rb (never returns to pre-Restriction Point) and one with hypophosphorylated Rb (uncommitted, pre-Restriction Point); T373 of Rb is preferentially phosphorylated first by CDK2/CDK4/6 due to slower dephosphorylation; T373-phosphorylated Rb remains chromatin-bound; p21 levels in G2 predict daughters' Rb phosphorylation state post-mitosis. Single-cell live imaging (E2F/CDK2 reporters), western blot, flow cytometry, phosphosite analysis PNAS High 30111539
2021 RB1-defective cancer cells show selective hypersensitivity to PARP1/2 inhibitors; PARPi sensitivity is associated with rapid activation of DNA replication checkpoint signaling and requires active DNA replication; sensitivity is independent of canonical homologous recombination defect signatures and exceeds that seen in BRCA-mutated backgrounds. Cancer cell line panel, xenograft mouse model, DNA replication checkpoint assays, engineered RB1 loss Nature communications High 34862364
2024 Cells enter a primed intermediate E2F activity state during G1 where Rb is singly phosphorylated at T373 by CDK2 or CDK4/6; T373-phosphorylated Rb remains chromatin-bound; full Rb hyperphosphorylation at multiple sites dissociates Rb from chromatin and fully activates E2F; this intermediate state is reversible, allowing cells to return to quiescence before the positive feedback loop commits them to proliferation. Single-cell E2F/CDK2 activity reporters, phospho-specific antibodies, chromatin fractionation, CDK inhibitor experiments Nature High 38926571
2006 An E2F-binding-deficient Rb1 mutant (R654W) in mice exhibits the same cell cycle defects as Rb1 null embryos, but survives at least 2 days longer with improved erythrocyte and fetal liver macrophage differentiation, demonstrating that Rb makes cell-type-specific contributions to differentiation that are genetically separable from its E2F1/2/3-mediated cell cycle control. Knock-in mouse (R654W point mutation), embryo survival analysis, cell differentiation assays Molecular and cellular biology High 16449662
2009 RB1CC1 (FIP200) nuclear protein directly binds the RB1 promoter at a GC-rich region 201 bp upstream of ATG and activates RB1 transcription; C-terminus of RB1CC1 is required for nuclear localization and promoter activation. Chromatin immunoprecipitation, luciferase reporter assay, EMSA, western blot International journal of cancer Medium 19437535
2012 Arf cooperates with Rb loss in mouse retinoblastoma; CGH reveals CDKN2A deletions in both human and mouse retinoblastoma; genetic analyses show Arf (not p16INK4A) is the critical cooperating tumor suppressor; Arf cooperation occurs through the p53 pathway, as p53 inactivation eliminates selection for Arf LOH. Array CGH, mouse genetic crosses (Rb/p107/Arf compound mutants), LOH analysis Journal of Clinical Investigation High 22484813
1998 Induction of oncogenic Ras in primary cells causes permanent G1 arrest (premature senescence) accompanied by p53 and p16INK4a accumulation; inactivation of either p53 or p16 (which acts through Rb) prevents Ras-induced arrest, placing Rb downstream of p16 in the senescence pathway. Retroviral transduction of primary cells, immunofluorescence, western blot, genetic inactivation (p53/p16 loss) Cell High 9054499

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 The hallmarks of cancer. Cell 19420 10647931
1997 Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 4238 9054499
1989 The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science (New York, N.Y.) 2754 2537532
2013 ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in medicine : official journal of the American College of Medical Genetics 1945 23788249
2003 Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 1823 12809602
1992 Effects of an Rb mutation in the mouse. Nature 1577 1406933
1988 SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell 1527 2839300
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1998 ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 1365 9529249
1993 The retinoblastoma protein associates with the protein phosphatase type 1 catalytic subunit. Genes & development 1351 8384581
1987 Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science (New York, N.Y.) 1329 3823889
2002 The RB and p53 pathways in cancer. Cancer cell 1273 12204530
1993 Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes & development 1214 8449399
1992 Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 1180 1406932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2003 Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays. Science (New York, N.Y.) 1117 14684825
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1989 Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. The EMBO journal 1051 2556261
1998 Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 1041 9468139
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
1992 Requirement for a functional Rb-1 gene in murine development. Nature 951 1406937
2006 RB and cell cycle progression. Oncogene 930 16936740
1999 Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 848 10499802
1998 Rb interacts with histone deacetylase to repress transcription. Cell 830 9491888
1993 Physical interaction of the retinoblastoma protein with human D cyclins. Cell 800 8490963
1998 Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature 780 9468140
2000 DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nature genetics 766 10615135
2000 DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nature genetics 755 10888886
2001 The Rb/E2F pathway and cancer. Human molecular genetics 740 11257102
2001 Rb targets histone H3 methylation and HP1 to promoters. Nature 720 11484059
1993 Interaction of myogenic factors and the retinoblastoma protein mediates muscle cell commitment and differentiation. Cell 709 8381715
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