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retinoblastoma-associated protein (pRb, Rb, pp110, p105-Rb, p110Rb, RB1)

Function: - may associate with the DNA replication complex - regulates entry into cell division - tumor suppressor - transcription repressor of E2F1 target genes - underphosphorylated, active form of RB1 interacts with E2F1 & represses its transcription activity, leading to cell cycle arrest - directly involved in heterochromatin formation by maintaining overall chromatin structure, epspecilly constitutive heterochromatin by stabilizing histone methylation - recruits & targets histone methyltransferases SUV39H1, SUV420H1 & SUV420H2, leading to epigenetic transcriptional repression - controls histone H4 Lys-20 trimethylation - inhibits the intrinsic kinase activity of TAF1 - in case of viral infections, interactions with SV40 large T antigen, HPV E7 protein or adenovirus E1A protein induce the disassembly of RB1-E2F1 complex thus disrupting RB1's activity - binds to UBF1 via one of the UBF1 HMG boxes thus inhibiting transcription of rDNA by RNA polymerase-1 (4b). - since UBF1 is required for transcription from TATA-containing promoters, binding to UBF1 may also generally affect RNA-polymerase 2 transcription of TATA box-containing genes - RB1 can repress transcription by RNA polymerase 3 [6] - interacts with ATAD5 (putative) - hypophosphorylated form interacts with & sequesters E2F1 - unphosphorylated form interacts with ARID3B, JARID1A, SUV39H1, MJD2A/JHDM3A & THOC1 - interacts with N-terminal domain of TAF1 - interacts with AATF, DNMT1, LIN9, LMNA, SUV420H1, SUV420H2, PELP1 & TMPO-alpha - may interact with NDC80 - interacts with EID1 & UBR4 - interacts with ARID4A & JARID1B - interacts with E4F1 - interacts with adenovirus E1A protein, HPV E7 protein & SV40 large T antigen - phosphorylated in G1, thereby releasing E2F1 which is then able to activate cell growth - dephosphorylated at the late M phase - SV40 large T antigen, HPV E7 & adenovirus E1A bind to the underphosphorylated, active form of pRb Structure: belongs to the retinoblastoma protein (RB) family Compartment: nucleus Expression: expressed in the retina Pathology: - defects in RB1 are the cause of childhood cancer retinoblastoma - defects in RB1 are a cause of a) bladder cancer b) osteogenic sarcoma Laboratory: - Retinoblastoma protein in tissue (by Immune stain) Comparative biology: - mice homozygous for an Rb mutation die in utero (E13.5-15.5) with defects in fetal hematopoiesis & widespread neuronal death [5]. - animals heterozygous for defective Rb protein are viable, but develop a variety of tumors - the most common neoplasms in Rb heterozygous mice are intermediate lobe pituitary tumors & medullary thyroid carcinomas - Rb & p53 mutations interact; mutant mice heterozygous for both p53 & Rb mutation have reduced viability & exhibit novel pathology including retinal dysplasia & increased tumor load & metastatic spread

Interactions

molecular events

Related

Rb-related protein p130; retinoblastoma-like protein 2; RBR-2; PRB2; 130 kD retinoblastoma-associated protein; p130 (RBL2 RB2) retinoblastoma binding protein 1; AT-rich interactive domain-containing protein 4A; ARID domain-containing protein 4A; RBBP-1 (ARID4A, RBBP1, RBP1) retinoblastoma binding protein 2; histone demethylase JARID1A; Jumonji/ARID domain-containing protein 1A; RBBP-2 (JARID1A, RBBP2, RBP2, KDM5A) retinoblastoma [Rb] gene (Rb1) retinoblastoma-associated protein-like p107 homolog; retinoblastoma-like protein 1; PRB1; 107 kD retinoblastoma-associated protein; p107 (RBL1)

General

anti-oncoprotein (tumor suppressor protein) nuclear protein phosphoprotein

Properties

SIZE: MW = 106-110 kD entity length = 928 aa COMPARTMENT: cell nucleus MOTIF: alanine-rich region {10-18} MOTIF: alanine residue (SEVERAL) proline-rich region SITE: 20-29 MOTIF: proline residue (SEVERAL) binding site SITE: N-TERMINAL FOR-BINDING-OF: death domain protein p84 Ser phosphorylation site {S249} FOR-PHOSPHORYLATION-BY: cyclin-dependent kinase-1 Thr phosphorylation site {T252} FOR-PHOSPHORYLATION-BY: cyclin-dependent kinase-1 Thr phosphorylation site {T356} Thr phosphorylation site {T373} FOR-PHOSPHORYLATION-BY: cyclin-dependent kinase-1 Pocket NAME: Pocket SITE: 373-771 FOR-BINDING-OF: nucleolar transcription factor 1 SV40 T antigen adenovirus E1a E2F histone deacetylase 1 MOTIF: domain A {373-579} spacer {580-639} domain B {640-771} Ser phosphorylation site {S807} FOR-PHOSPHORYLATION-BY: cyclin-dependent kinase Ser phosphorylation site {S811} FOR-PHOSPHORYLATION-BY: cyclin-dependent kinase Thr phosphorylation site {T826}

References

  1. Seizinger & Breakefield TINS 13(1) 3 (1990)
  2. Wilcock D, Lane DP. Localization of p53, retinoblastoma and host replication proteins at sites of viral replication in herpes-infected cells. Nature. 1991 Jan 31;349(6308):429-31. PMID: 1671528
  3. Hunter T. Cooperation between oncogenes. Cell. 1991 Jan 25;64(2):249-70. Review. PMID: 1988147
  4. Dynlacht BD. Retinoblastoma protein. Pol I gets repressed. Nature. 1995 Mar 9;374(6518):114. No abstract available. PMID: 7877677 - Cavanaugh AH, Hempel WM, Taylor LJ, Rogalsky V, Todorov G, Rothblum LI. Activity of RNA polymerase I transcription factor UBF blocked by Rb gene product. Nature. 1995 Mar 9;374(6518):177-80. PMID: 7877691
  5. Cordon-Cardo C. Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia. Am J Pathol. 1995 Sep;147(3):545-60. Review. PMID: 7677168
  6. White RJ, Trouche D, Martin K, Jackson SP, Kouzarides T. Repression of RNA polymerase III transcription by the retinoblastoma protein. Nature. 1996 Jul 4;382(6586):88-90. PMID: 8657311
  7. Entrez Gene :accession 5925
  8. RB1base; Note: RB1 mutation db http://rb1-lsdb.d-lohmann.de/
  9. Atlas of genetics & cytogenetics in oncology & haematology http://atlasgeneticsoncology.org/genes/RB1ID90.html
  10. GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=RB1
  11. Wikipedia; Note: retinoblastoma protein entry http://en.wikipedia.org/wiki/retinoblastoma_protein
  12. UniProt :accession P06400

Component-of

molecular complex

Databases & Figures

OMIM correlations UniProt P06400 PFAM correlations Entrez Gene 5925 Kegg hsa:5925 Figures/diagrams/slides/tables related to retinoblastoma-associated protein