Retinoblastoma 1 (including osteosarcoma)
PDB rendering based on 1ad6.
Available structures
1ad6, 1gh6, 1gux, 1o9k, 2aze
Identifiers
Symbols	RB1; OSRC; RB
External IDs	OMIM: 180200 MGI: 97874 HomoloGene: 272
Gene ontology Molecular function • molecular_function • transcription factor activity • transcription coactivator activity • transcription factor binding • transcription repressor activity • kinase binding • androgen receptor binding Cellular component • chromatin • nucleus • transcription factor complex • spindle Biological process • cell cycle checkpoint • G1/S transition of mitotic cell cycle • negative regulation of transcription from RNA polymerase II promoter • M phase • transcription • regulation of transcription, DNA-dependent • negative regulation of protein kinase activity • cell cycle • cell cycle arrest • negative regulation of cell proliferation • negative regulation of cell growth • androgen receptor signaling pathway • regulation of lipid kinase activity • positive regulation of transcription from RNA polymerase II promoter • striated muscle cell differentiation • cell division • G1 phase
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5925	19645
Ensembl	ENSG00000139687	ENSMUSG00000022105
UniProt	P06400	Q3UFM7
RefSeq	NM_000321 (mRNA)	NM_009029 (mRNA)
	NP_000312 (protein)	NP_033055 (protein)
Location	Chr 13: 47.78 - 47.95 Mb	Chr 14: 71.93 - 72.06 Mb
PubMed search	[1]	[2]

The retinoblastoma protein (abbreviated pRb or Rb) is a tumor suppressor protein that is dysfunctional in many types of cancer.^[1] One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide.

pRb belongs to the pocket protein family, whose members have a pocket for the functional binding of other proteins.^[2][3] Should an oncogenic protein, such as those produced by cells infected by high-risk types of human papillomaviruses, bind and inactivate pRb, this can lead to cancer.

[edit] Name and genetics

In humans, the protein is encoded by the RB1 gene located on 13q14.1-q14.2. If both alleles of this gene are mutated early in life, the protein is inactivated and results in development of retinoblastoma cancer, hence the name Rb. It is not known why an eye cancer results from a mutation in a gene that is important all over the body.

Two forms of retinoblastoma were noticed: a bilateral, familial form and a unilateral, sporadic form. Sufferers of the former were 6 times more likely to develop other types of cancer later in life^[4]. This highlighted the fact that mutated Rb could be inherited and lent support to the two-hit hypothesis. This states that only one working allele of a tumour suppressor gene is necessary for its function (the mutated gene is recessive), and so both need to be mutated before the cancer phenotype will appear. In the familial form, a mutated allele is inherited along with a normal allele. In this case, should a cell sustain only one mutation in the other RB gene, all pRb in that cell would be ineffective at inhibiting cell cycle progression, allowing cells to divide uncontrollably and eventually become cancerous. Furthermore, as one allele is already mutated in all other somatic cells, the future incidence of cancers in these individuals is observed with linear kinetics^[5]. The working allele need not undergo a mutation per se, as loss of heterozygosity (LOH) is frequently observed in such tumours.

However, in the sporadic form, both alleles would need to sustain a mutation before the cell can become cancerous. This explains why sufferers of sporadic retinoblastoma are not at increased risk of cancers later in life, as both alleles are functional in all their other cells. Future cancer incidence in sporadic Rb cases is observed with polynomial kinetics, not exactly quadratic as expected because the first mutation must arise through normal mechanisms, and then can be duplicated by LOH to result in a tumour progenitor.

RB1 orthologs ^[6] have also been identified in most mammals for which complete genome data are available.

[edit] Cell cycle suppression

pRb prevents the cell from replicating damaged DNA by preventing its progression along the cell cycle through G1 (first gap phase) into S (synthesis phase).^[7] pRb binds and inhibits transcription factors of the E2F family, which are composed of dimers of an E2F protein and a DP protein.^[8] The transcription activating complexes of E2 promoter-binding–protein-dimerization partners (E2F-DP) can push a cell into S phase.^{[9][10][11][12][13]} As long as E2F-DP is inactivated, the cell remains stalled in the G1 phase. When pRb is bound to E2F, the complex acts as a growth suppressor and prevents progression through the cell cycle.^[3] The pRb-E2F/DP complex also attracts a histone deacetylase (HDAC) protein to the chromatin, reducing transcription of S phase promoting factors, further suppressing DNA synthesis.

[edit] Activation and inactivation

In the hypophosphorylated state, pRb is active and carries out its role as tumor suppressor by inhibiting cell cycle progression. Phosphorylation inactivates pRb,during the M-to-G1 transition, pRb is progressively dephosphorylated by PP1, returning to its growth-suppressive hypophosphorylated state .^[3][14]

When it is time for a cell to enter S phase, complexes of cyclin-dependent kinases (CDK) and cyclins phosphorylate pRb, inhibiting its activity.^{[2][3][7][15]} The initial phosphorylation is performed by Cyclin D/CDK4/CDK6 and followed by additional phosphorylation by Cyclin E/CDK2. pRb remains phosphorylated throughout S, G2 and M phases.^[3]

Phosphorylation of pRb allows E2F-DP to dissociate from pRb and become active.^[3][10][7] When E2F is free it activates factors like cyclins (e.g. Cyclin E and A), which push the cell through the cell cycle by activating cyclin-dependent kinases, and a molecule called proliferating cell nuclear antigen, or PCNA, which speeds DNA replication and repair by helping to attach polymerase to DNA.^[9][7][12]

[edit] Interactions

Retinoblastoma protein has been shown to interact with Polymerase (DNA directed), alpha 1,^[16] LIN9,^[17] CUTL1,^[18] E2F2,^[19] Cyclin T2,^[20] RBBP8,^[21][22] E2F1,^{[23][24][25][26][27][28][29]} RBBP7,^[30][31] PRDM2,^[32] ARID4A,^[33] MRFAP1,^[34][24] RBBP4,^[23][31][35] JARID1A,^[36][37] BRF1,^[38][39] BRCA1,^[40][41][30] Abl gene,^[42][43] C-Raf,^[44][45] Cyclin A1,^[46] MORF4L1,^[34][24] Cyclin D1,^[47][48] Prohibitin,^[45][49] E4F1,^[26] Aryl hydrocarbon receptor,^[50] DNMT1,^[51] HDAC3,^[52][33] FRK,^[53] Plasminogen activator inhibitor-2,^[54] SUV39H1,^[55][56] NCOA6,^[57] SNAPC1,^[58] THOC1,^[59] HDAC1,^{[21][60][61][62][63][33][64]} Histone deacetylase 2,^[33] SNAPC3,^[58] PA2G4,^[65] SNW1,^[66] Androgen receptor,^[67][68] RBBP9,^[69] ENC1,^[70] MCM7,^[71] PIK3R3,^[72] TRAP1,^[73] CDK9,^[20] TAF1,^{[47][74][75][76]} PRKRA,^[77] UBTF,^[78] EID1,^[79][80] Apoptosis antagonizing transcription factor,^[81][82] TRIP11,^[83] Peroxisome proliferator-activated receptor gamma,^[52] MyoD,^[84][85] USP4,^[86] C-jun,^[87] Promyelocytic leukemia protein^[88] and HBP1.^[89]

Overview of signal transduction pathways involved in apoptosis.

[edit] See also

• p53 - involved in the DNA repair support function of pRb
• Transcription coregulator
• Retinoblastoma

[edit] References

[edit] Further reading

v • d • e PDB Gallery 1ad6: DOMAIN A OF HUMAN RETINOBLASTOMA TUMOR SUPPRESSOR   1gh6: RETINOBLASTOMA POCKET COMPLEXED WITH SV40 LARGE T ANTIGEN   1gux: RB POCKET BOUND TO E7 LXCXE MOTIF   1o9k: CRYSTAL STRUCTURE OF THE RETINOBLASTOMA TUMOUR SUPPRESSOR PROTEIN BOUND TO E2F PEPTIDE   2aze: Structure of the Rb C-terminal domain bound to an E2F1-DP1 heterodimer

[edit] External links

• MeSH RB1+protein,+human
• MeSH Retinoblastoma+genes
• Retinoblastoma Genetics
• There is a diagram of the pRb-E2F interactions here.

This article on a gene on chromosome 13 is a stub. You can help Wikipedia by expanding it. v • d • e

This article incorporates text from the United States National Library of Medicine, which is in the public domain.