Retinoblastoma protein

RB1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesRB1, pRb, RB, retinoblastoma 1, OSRC, PPP1R130, p105-Rb, pp110, Retinoblastoma protein, RB transcriptional corepressor 1
External IDsMGI: 97874 HomoloGene: 272 GeneCards: RB1
Gene location (Human)
Chr.Chromosome 13 (human)[1]
BandNo data availableStart48,303,751 bp[1]
End48,481,986 bp[1]
RNA expression pattern


More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

5925

19645

Ensembl

ENSG00000139687

ENSMUSG00000022105

UniProt

P06400

P13405

RefSeq (mRNA)

NM_000321

NM_009029

RefSeq (protein)

NP_000312
NP_000312.2

NP_033055

Location (UCSC)Chr 13: 48.3 – 48.48 MbChr 13: 73.18 – 73.33 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The retinoblastoma protein (protein name abbreviated pRb; gene name abbreviated RB or RB1) is a tumor suppressor protein that is dysfunctional in several major cancers.[5] One function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. When the cell is ready to divide, pRb is phosphorylated, becomes inactive and allows cell cycle progression. It is also a recruiter of several chromatin remodeling enzymes such as methylases and acetylases.[6]

Rb belongs to the pocket protein family, whose members have a pocket for the functional binding of other proteins.[7][8] 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. The RB gene may have been responsible for the evolution of multicellularity in several lineages of life including animals.[9]

Name and genetics

In humans, the protein is encoded by the RB1 gene located on chromosome 13 -- more specifically, 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. Retinal cells are not sloughed off or replaced, and are subjected to high levels of mutagenic UV radiation, and thus most pRB knock-outs occur in retinal tissue (but it's also been documented in certain skin cancers in patients from New Zealand where the amount of UV radiation is significantly higher).

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.[10] 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 Rb 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.[11] 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[12] have also been identified in most mammals for which complete genome data are available.

RB/E2F-family proteins repress transcription.[13]

Cell cycle suppression

Rb restricts the cell's ability to replicate DNA by preventing its progression from the G1 (first gap phase) to S (synthesis phase) phase of the cell division cycle.[14] Rb binds and inhibits transcription factors of the E2F family, which are composed of dimers of an E2F protein and a dimerization partner (DP) protein.[15] The transcription activating complexes of E2 promoter-binding–protein-dimerization partners (E2F-DP) can push a cell into S phase.[16][17][18][19][20] As long as E2F-DP is inactivated, the cell remains stalled in the G1 phase. When Rb is bound to E2F, the complex acts as a growth suppressor and prevents progression through the cell cycle.[8] The Rb-E2F/DP complex also attracts a histone deacetylase (HDAC) protein to the chromatin, reducing transcription of S phase promoting factors, further suppressing DNA synthesis.

Detection

Several methods for detecting the RB1 gene mutations have been developed[21] including a method that can detect large deletions that correlate with advanced stage retinoblastoma.[22]

Activation and inactivation

Rb is phosphorylated to pRb by certain cyclin-dependent kinases (CDKs). pRb is described as being hyperphosphorylated and when in this state, it is unable to bind to complex E2F and therefore, unable to restrict progression from the G1 phase to the S phase of the cell cycle. During the M-to-G1 transition, pRb is progressively dephosphorylated by PP1, returning to its growth-suppressive hypophosphorylated state Rb .[8][23]

When it is time for a cell to enter S phase, complexes of cyclin-dependent kinases (CDK) and cyclins phosphorylate Rb to pRb, inhibiting its activity.[7][8][24][25] 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.[8]

Phosphorylation of Rb allows E2F-DP to dissociate from pRb and become active.[8][17][24] 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.[16][19][24]

Rb family proteins are components of the DREAM complex (also named LINC complex), which is composed of LIN9, LIN54, LIN37, MYBL2, RBL1, RBL2, RBBP4, TFDP1, TFDP2, E2F4 and E2F5. There is a testis-specific version of the complex, where LIN54, MYBL2 and RBBP4 are replaced by MTL5, MYBL1 and RBBP7, respectively. In Drosophila both DREAM versions also exist, the components being mip130 (lin9 homolog, replaced by aly in testes), mip120 (lin54 homolog, replaced by tomb in testes), and Myb, Caf1p55, DP, Mip40, E2F2, Rbf and Rbf2. The DREAM complex exists in quiescent cells in association with MuvB (consisting of HDAC1 or HDAC2, LIN52 and L3mbtl1, L3mbtl3 or L3mbtl4) where it represses cell cycle-dependent genes. DREAM dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2.

Regeneration

Cochlea

The retinoblastoma protein is involved in the growth and development of mammalian hair cells of the cochlea, and appears to be related to the cells' inability to regenerate. Embryonic hair cells require Rb, among other important proteins, to exit the cell-cycle and stop dividing, which allows maturation of the auditory system. Once wild-type mammals have reached adulthood, their cochlear hair cells become incapable of proliferation. In studies where the gene for Rb is deleted in mice cochlea, hair cells continue to proliferate in early adulthood. Though this may seem to be a positive development, Rb-knockdown mice tend to develop severe hearing loss due to degeneration of the organ of Corti. For this reason, Rb seems to be instrumental for completing the development of mammalian hair cells and keeping them alive.[26][27] However, it is clear that without Rb, hair cells have the ability to proliferate, which is why Rb is known as a tumor suppressor. Temporarily and precisely turning off Rb in adult mammals with damaged hair cells may lead to propagation and therefore successful regeneration. Suppressing function of the retinoblastoma protein in the adult rat cochlea has been found to cause proliferation of supporting cells and hair cells. Rb can be downregulated by activating the sonic hedgehog pathway, which phosphorylates the proteins and reduces gene transcription.[28]

Neurons

Disrupting Rb expression in vitro, either by gene deletion or knockdown of Rb short interfering RNA, causes dendrites to branch out farther. In addition, Schwann cells, which provide essential support for the survival of neurons, travel with the neurites, extending farther than normal. The inhibition of Rb supports the continued growth of nerve cells.[29]

Interactions

Retinoblastoma protein has been shown to interact with:

Overview of signal transduction pathways involved in apoptosis.

See also

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000139687 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000022105 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. ↑ Murphree AL, Benedict WF (March 1984). "Retinoblastoma: clues to human oncogenesis". Science. 223 (4640): 1028–33. PMID 6320372. doi:10.1126/science.6320372.
  6. ↑ Shao Z, Robbins PD (1995). "Differential regulation of E2F and Sp1-mediated transcription by G1 cyclins". Oncogene. 10 (2): 221–8. PMID 7838522.
  7. 1 2 Korenjak M, Brehm A (October 2005). "E2F-Rb complexes regulating transcription of genes important for differentiation and development". Current Opinion in Genetics & Development. 15 (5): 520–7. PMID 16081278. doi:10.1016/j.gde.2005.07.001.
  8. 1 2 3 4 5 6 Münger K, Howley PM (November 2002). "Human papillomavirus immortalization and transformation functions". Virus Res. 89 (2): 213–28. PMID 12445661. doi:10.1016/S0168-1702(02)00190-9.
  9. ↑ https://futurism.com/multicellular-life-caused-one-gene-gene-suppresses-cancer/
  10. ↑ Kleinerman RA, Tucker MA, Tarone RE, Abramson DH, Seddon JM, Stovall M, Li FP, Fraumeni JF (April 2005). "Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up". J. Clin. Oncol. 23 (10): 2272–9. PMID 15800318. doi:10.1200/JCO.2005.05.054.
  11. ↑ Knudson AG (April 1971). "Mutation and Cancer: Statistical Study of Retinoblastoma". Proc. Natl. Acad. Sci. U.S.A. 68 (4): 820–3. PMC 389051 Freely accessible. PMID 5279523. doi:10.1073/pnas.68.4.820.
  12. ↑ "OrthoMaM phylogenetic marker: RB1 coding sequence".
  13. ↑ Frolov MV, Dyson NJ (May 2004). "Molecular mechanisms of E2F-dependent activation and RB-mediated repression". J. Cell. Sci. 117 (Pt 11): 2173–81. PMID 15126619. doi:10.1242/jcs.01227.
  14. ↑ Goodrich DW, Wang NP, Qian YW, Lee EY, Lee WH (November 1991). "The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle". Cell. 67 (2): 293–302. PMID 1655277. doi:10.1016/0092-8674(91)90181-w.
  15. ↑ Wu CL, Zukerberg LR, Ngwu C, Harlow E, Lees JA (May 1995). "In vivo association of E2F and DP family proteins". Mol. Cell. Biol. 15 (5): 2536–46. PMC 230484 Freely accessible. PMID 7739537. doi:10.1128/mcb.15.5.2536.
  16. 1 2 Funk J.O.; Waga S.; Harry J.B.; Espling E.; Stillman B.; Galloway D.A. (1997). "Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein". Trends in Genetics. 13 (12): 474. doi:10.1016/0168-9525(97)90029-9.
  17. 1 2 De Veylder L, Joubès J, Inzé D (December 2003). "Plant cell cycle transitions". Current Opinion in Plant Biology. 6 (6): 536–43. PMID 14611951. doi:10.1016/j.pbi.2003.09.001.
  18. ↑ de Jager SM, Maughan S, Dewitte W, Scofield S, Murray JA (June 2005). "The developmental context of cell-cycle control in plants". Semin. Cell Dev. Biol. 16 (3): 385–96. PMID 15840447. doi:10.1016/j.semcdb.2005.02.004.
  19. 1 2 Greenblatt RJ (2005). "Human papillomaviruses: Diseases, diagnosis, and a possible vaccine". Clinical Microbiology Newsletter. 27 (18): 139–45. doi:10.1016/j.clinmicnews.2005.09.001.
  20. ↑ Sinal SH, Woods CR (October 2005). "Human papillomavirus infections of the genital and respiratory tracts in young children". Semin Pediatr Infect Dis. 16 (4): 306–16. PMID 16210110. doi:10.1053/j.spid.2005.06.010.
  21. ↑ Parsam VL, Kannabiran C, Honavar S, Vemuganti GK, Ali MJ (December 2009). "A comprehensive, sensitive and economical approach for the detection of mutations in the RB1 gene in retinoblastoma" (PDF). J. Genet. 88 (4): 517–27. PMID 20090211. doi:10.1007/s12041-009-0069-z.
  22. ↑ Ali MJ, Parsam VL, Honavar SG, Kannabiran C, Vemuganti GK, Reddy VA (2010). "RB1 gene mutations in retinoblastoma and its clinical correlation". Saudi Journal of Ophthalmology. 24 (4): 119–123. PMID 23960888. doi:10.1016/j.sjopt.2010.05.003.
  23. ↑ Vietri M, Bianchi M, Ludlow JW, Mittnacht S, Villa-Moruzzi E (2006). "Direct interaction between the catalytic subunit of Protein Phosphatase 1 and pRb". Cancer Cell Int. 6: 3. PMC 1382259 Freely accessible. PMID 16466572. doi:10.1186/1475-2867-6-3.
  24. 1 2 3 Das SK, Hashimoto T, Shimizu K, Yoshida T, Sakai T, Sowa Y, Komoto A, Kanazawa K (November 2005). "Fucoxanthin induces cell cycle arrest at G0/G1 phase in human colon carcinoma cells through up-regulation of p21WAF1/Cip1". Biochim. Biophys. Acta. 1726 (3): 328–35. PMID 16236452. doi:10.1016/j.bbagen.2005.09.007.
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  27. ↑ Weber T, Corbett MK, Chow LM, Valentine MB, Baker SJ, Zuo J (2008). "Rapid cell-cycle reentry and cell death after acute inactivation of the retinoblastoma gene product in postnatal cochlear hair cells". Proc. Natl. Acad. Sci. U.S.A. 105 (2): 781–5. PMC 2206613 Freely accessible. PMID 18178626. doi:10.1073/pnas.0708061105.
  28. ↑ Lu N, Chen Y, Wang Z, Chen G, Lin Q, Chen ZY, Li H (2013). "Sonic hedgehog initiates cochlear hair cell regeneration through downregulation of retinoblastoma protein". Biochem. Biophys. Res. Commun. 430 (2): 700–5. PMC 3579567 Freely accessible. PMID 23211596. doi:10.1016/j.bbrc.2012.11.088.
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  30. ↑ Miyamura T, Nishimura J, Yufu Y, Nawata H (February 1997). "Interaction of BCR-ABL with the retinoblastoma protein in Philadelphia chromosome-positive cell lines". Int. J. Hematol. 65 (2): 115–21. PMID 9071815. doi:10.1016/S0925-5710(96)00539-7.
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  36. 1 2 3 4 Lai A, Lee JM, Yang WM, DeCaprio JA, Kaelin WG, Seto E, Branton PE (October 1999). "RBP1 Recruits Both Histone Deacetylase-Dependent and -Independent Repression Activities to Retinoblastoma Family Proteins". Mol. Cell. Biol. 19 (10): 6632–41. PMC 84642 Freely accessible. PMID 10490602. doi:10.1128/mcb.19.10.6632.
  37. ↑ Ge NL, Elferink CJ (August 1998). "A direct interaction between the aryl hydrocarbon receptor and retinoblastoma protein. Linking dioxin signaling to the cell cycle". J. Biol. Chem. 273 (35): 22708–13. PMID 9712901. doi:10.1074/jbc.273.35.22708.
  38. ↑ Aprelikova ON, Fang BS, Meissner EG, Cotter S, Campbell M, Kuthiala A, Bessho M, Jensen RA, Liu ET (October 1999). "BRCA1-associated growth arrest is RB-dependent". Proc. Natl. Acad. Sci. U.S.A. 96 (21): 11866–71. PMC 18378 Freely accessible. PMID 10518542. doi:10.1073/pnas.96.21.11866.
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  40. 1 2 Yarden RI, Brody LC (April 1999). "BRCA1 interacts with components of the histone deacetylase complex". Proc. Natl. Acad. Sci. U.S.A. 96 (9): 4983–8. PMC 21803 Freely accessible. PMID 10220405. doi:10.1073/pnas.96.9.4983.
  41. ↑ Johnston IM, Allison SJ, Morton JP, Schramm L, Scott PH, White RJ (June 2002). "CK2 Forms a Stable Complex with TFIIIB and Activates RNA Polymerase III Transcription in Human Cells". Mol. Cell. Biol. 22 (11): 3757–68. PMC 133823 Freely accessible. PMID 11997511. doi:10.1128/MCB.22.11.3757-3768.2002.
  42. ↑ Sutcliffe JE, Cairns CA, McLees A, Allison SJ, Tosh K, White RJ (June 1999). "RNA Polymerase III Transcription Factor IIIB Is a Target for Repression by Pocket Proteins p107 and p130". Mol. Cell. Biol. 19 (6): 4255–61. PMC 104385 Freely accessible. PMID 10330166. doi:10.1128/mcb.19.6.4255.
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  45. 1 2 Wang S, Nath N, Fusaro G, Chellappan S (November 1999). "Rb and Prohibitin Target Distinct Regions of E2F1 for Repression and Respond to Different Upstream Signals". Mol. Cell. Biol. 19 (11): 7447–60. PMC 84738 Freely accessible. PMID 10523633. doi:10.1128/mcb.19.11.7447.
  46. 1 2 Simone C, Bagella L, Bellan C, Giordano A (June 2002). "Physical interaction between pRb and cdk9/cyclinT2 complex". Oncogene. 21 (26): 4158–65. PMID 12037672. doi:10.1038/sj.onc.1205511.
  47. ↑ Gupta S, Luong MX, Bleuming SA, Miele A, Luong M, Young D, Knudsen ES, Van Wijnen AJ, Stein JL, Stein GS (September 2003). "Tumor suppressor pRB functions as a co-repressor of the CCAAT displacement protein (CDP/cut) to regulate cell cycle controlled histone H4 transcription". J. Cell. Physiol. 196 (3): 541–56. PMID 12891711. doi:10.1002/jcp.10335.
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  50. ↑ Dowdy SF, Hinds PW, Louie K, Reed SI, Arnold A, Weinberg RA (May 1993). "Physical interaction of the retinoblastoma protein with human D cyclins". Cell. 73 (3): 499–511. PMID 8490963. doi:10.1016/0092-8674(93)90137-F.
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  52. 1 2 Nicolas E, Ait-Si-Ali S, Trouche D (August 2001). "The histone deacetylase HDAC3 targets RbAp48 to the retinoblastoma protein". Nucleic Acids Res. 29 (15): 3131–6. PMC 55834 Freely accessible. PMID 11470869. doi:10.1093/nar/29.15.3131.
  53. 1 2 3 Pardo PS, Leung JK, Lucchesi JC, Pereira-Smith OM (December 2002). "MRG15, a novel chromodomain protein, is present in two distinct multiprotein complexes involved in transcriptional activation". J. Biol. Chem. 277 (52): 50860–6. PMID 12397079. doi:10.1074/jbc.M203839200.
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  55. 1 2 Fajas L, Paul C, Zugasti O, Le Cam L, Polanowska J, Fabbrizio E, Medema R, Vignais ML, Sardet C (July 2000). "pRB binds to and modulates the transrepressing activity of the E1A-regulated transcription factor p120E4F". Proc. Natl. Acad. Sci. U.S.A. 97 (14): 7738–43. PMC 16614 Freely accessible. PMID 10869426. doi:10.1073/pnas.130198397.
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  57. ↑ Wu CL, Zukerberg LR, Ngwu C, Harlow E, Lees JA (May 1995). "In vivo association of E2F and DP family proteins". Mol. Cell. Biol. 15 (5): 2536–46. PMC 230484 Freely accessible. PMID 7739537. doi:10.1128/mcb.15.5.2536.
  58. ↑ Taniura H, Taniguchi N, Hara M, Yoshikawa K (January 1998). "Necdin, a postmitotic neuron-specific growth suppressor, interacts with viral transforming proteins and cellular transcription factor E2F1". J. Biol. Chem. 273 (2): 720–8. PMID 9422723. doi:10.1074/jbc.273.2.720.
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  61. ↑ MacLellan WR, Xiao G, Abdellatif M, Schneider MD (December 2000). "A Novel Rb- and p300-Binding Protein Inhibits Transactivation by MyoD". Mol. Cell. Biol. 20 (23): 8903–15. PMC 86545 Freely accessible. PMID 11073990. doi:10.1128/MCB.20.23.8903-8915.2000.
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  65. 1 2 Dick FA, Sailhamer E, Dyson NJ (May 2000). "Mutagenesis of the pRB Pocket Reveals that Cell Cycle Arrest Functions Are Separable from Binding to Viral Oncoproteins". Mol. Cell. Biol. 20 (10): 3715–27. PMC 85672 Freely accessible. PMID 10779361. doi:10.1128/MCB.20.10.3715-3727.2000.
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