Retinoblastoma protein

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Retinoblastoma 1 (including osteosarcoma)
PDB rendering based on 1ad6.
Available structures: 1ad6, 1gh6, 1gux, 1o9k, 2aze
Identifiers
Symbol(s) RB1; OSRC; RB
External IDs OMIM: 180200 MGI: 97874 Homologene: 272
RNA expression pattern

Image:PBB GE RB1 203132 at.png

Image:PBB GE RB1 211540 s at.png

More reference expression data

Orthologs
Human Mouse
Entrez 5925 19645
Ensembl ENSG00000139687 ENSMUSG00000022105
Uniprot P06400 Q3UFM7
Refseq NM_000321 (mRNA)
NP_000312 (protein) 		NM_009029 (mRNA)
NP_033055 (protein)
Location Chr 13: 47.78 - 47.95 Mb Chr 14: 71.93 - 72.06 Mb
Pubmed search [1] [2]

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Overview

The retinoblastoma protein, also called pRb or Rb, is a tumor suppressor protein found to be dysfunctional in a number of types of cancer.[1] pRb was so named because retinoblastoma cancer results when the protein is inactivated by a mutation in both alleles of the RB1 gene that codes for it. The "p" in pRb stands for protein and is a way to distinguish it from the gene, Rb. pRb is usually present as a phosphoprotein inside cells and is a target for phosphorylation by several kinases as described below. One highly studied function of pRb is to prevent the cell from dividing or progressing through the cell cycle. Thus, when pRb is ineffective at this role, mutated cells can continue to divide and may become cancerous.

pRb is a member of the 'Pocket protein family', because it has a pocket to which proteins can bind.[2][3] Oncogenic proteins such as those produced by cells infected by high-risk types of human papillomaviruses can bind and inactivate pRb, which can lead to cancer.

Cell cycle suppression

pRb prevents the cell from replicating damaged DNA by preventing its progression through the cell cycle into its S, or synthesis phase or progressing through G1, or first gap phase.[4] pRb binds and inhibits transcription factors of the E2F family. E2F transcription factors are dimers of an E2F protein and a DP protein.[5] The transcription activating complexes of E2 promoter-binding–protein-dimerization partners (E2F-DP) can push a cell into S phase.[6][7][8][9][10] 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, further suppressing DNA synthesis.

Activation and inactivation

pRb can actively inhibit cell cycle progression when it is dephosphorylated while this function is inactivated when pRb is phosphorylated. pRb is activated near the end of G1 phase when a phosphatase dephosphorylates it, allowing it to bind E2F.[3][11]

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][4][12] The initial phosphorylation is performed by Cyclin D/CDK4,6 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][7][4] When E2F is freed 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.[6][4][9]

See also

References

  1. ↑ Murphree A.L. and Benedict W.F. 1984. Retinoblastoma: clues to human oncogenesis in Science, 223(4640): 1028-1033. Entrez PubMed 6320372 Retrieved on January 24, 2007.
  2. ↑ 2.0 2.1 Korenjak M. and Brehm A. 2005. E2F–Rb complexes regulating transcription of genes important for differentiation and development. Current Opinion in Genetics & Development, 15(5): 520-527.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Münger K. and Howley P.M. 2002. Human papillomavirus immortalization and transformation functions. Virus Research, 89: 213–228.
  4. ↑ 4.0 4.1 4.2 4.3 Das S.K., Hashimoto T., Shimizu K., Yoshida T., Sakai T., Sowa Y., Komoto A., and Kanazawa K. 2005. Fucoxanthin induces cell cycle arrest at G0/G1 phase in human colon carcinoma cells through up-regulation of p21WAF1/Cip1. Biochimica et Biophysica Acta, 1726(3):328-335. PMID 16236452. Retrieved on January 24, 2007.
  5. ↑ Wu C.L., Zukerberg L.R., Ngwu C., Harlow E. and Lees J.A. 1995. In vivo association of E2F and DP family proteins. Molecular and Cellular Biology 15(5): 2536-2546. Entrez PubMed 7739537 Retrieved on January 24, 2007.
  6. ↑ 6.0 6.1 Funk J.O., Waga S., Harry J.B., Espling E., Stillman B., and 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.
  7. ↑ 7.0 7.1 De Veylder L., Joubès J., and Inzé D. 2003. Plant cell cycle transitions. Current Opinion in Plant Biology. 6(6): 536-543.
  8. ↑ de Jager S.M., Maughan S., Dewitte W., Scofield S., and Murray J.A.H. 2005. The developmental context of cell-cycle control in plants. Seminars in Cell & Developmental Biology. 16(3): 385-396. PMID 15840447. Retrieved on January 24, 2007.
  9. ↑ 9.0 9.1 Greenblatt R.J. 2005. Human papillomaviruses: Diseases, diagnosis, and a possible vaccine. Clinical Microbiology Newsletter, 27(18): 139-145. doi:10.1016/j.clinmicnews.2005.09.001. Retrieved on January 24, 2007.
  10. ↑ Sinal S.H. and Woods C.R. 2005. Human papillomavirus infections of the genital and respiratory tracts in young children. Seminars in Pediatric Infectious Diseases, 16(4): 306-316. PMID 16210110. Retrieved on January 24, 2007.
  11. ↑ Vietri M., Bianchi M., Ludlow J.W., Mittnacht S. and Villa-Moruzzi E. 2006. Direct interaction between the catalytic subunit of Protein Phosphatase 1 and pRb. Cancer cell international, 6(3): 3 Entrez PubMed 16466572 Retrieved on January 24, 2007.
  12. ↑ Bartkova J., Grøn B., Dabelsteen E., and Bartek J. 2003. Cell-cycle regulatory proteins in human wound healing. Archives of Oral Biology, 48(2): 125-132. PMID 12642231. Retrieved on January 24, 2007.

Further reading

  • Momand J, Wu HH, Dasgupta G (2000). "MDM2--master regulator of the p53 tumor suppressor protein.". Gene 242 (1-2): 15-29. PMID 10721693.
  • Zheng L, Lee WH (2003). "Retinoblastoma tumor suppressor and genome stability.". Adv. Cancer Res. 85: 13-50. PMID 12374284.
  • Classon M, Harlow E (2003). "The retinoblastoma tumour suppressor in development and cancer.". Nat. Rev. Cancer 2 (12): 910-7. doi:10.1038/nrc950. PMID 12459729.
  • Lai H, Ma F, Lai S (2003). "Identification of the novel role of pRB in eye cancer.". J. Cell. Biochem. 88 (1): 121-7. doi:10.1002/jcb.10283. PMID 12461781.
  • Simin K, Wu H, Lu L, et al. (2006). "pRb inactivation in mammary cells reveals common mechanisms for tumor initiation and progression in divergent epithelia.". PLoS Biol. 2 (2): E22. doi:10.1371/journal.pbio.0020022. PMID 14966529.
  • Lohmann DR, Gallie BL (2004). "Retinoblastoma: revisiting the model prototype of inherited cancer.". American journal of medical genetics. Part C, Seminars in medical genetics 129 (1): 23-8. doi:10.1002/ajmg.c.30024. PMID 15264269.
  • Clemo NK, Arhel NJ, Barnes JD, et al. (2005). "The role of the retinoblastoma protein (Rb) in the nuclear localization of BAG-1: implications for colorectal tumour cell survival.". Biochem. Soc. Trans. 33 (Pt 4): 676-8. doi:10.1042/BST0330676. PMID 16042572.
  • Rodríguez-Cruz M, del Prado M, Salcedo M (2006). "[Genomic retinoblastoma perspectives: implications of tumor supressor gene RB1]". Rev. Invest. Clin. 57 (4): 572-81. PMID 16315642.
  • Knudsen ES, Knudsen KE (2006). "Retinoblastoma tumor suppressor: where cancer meets the cell cycle.". Exp. Biol. Med. (Maywood) 231 (7): 1271-81. PMID 16816134.


External links

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v • d • e
Transcription coregulators
CoactivatorsCARM1 - CRTC1 - CBP - NCOA1 (SRC-1) - NCOA2 (GRIP1/SRC-2/TIF2) - NCOA3 (AIB/SRC-3/TRAM-1) - NCOA4 - NCOA6 - NCOA7 - PPARGC1A - PPARGC1B - TGFB1I1
CorepressorsNCOR1 - NRIP1 - NCOR2 (SMRT) - PELP-1 - RCOR1 - Rb - SIN3A- SIN3B - Tripartite motif-containing (TRIM24, TRIM28)
ATP-dependent remodeling factorsChromatin Structure Remodeling (RSC) Complex - SWI/SNF
v • d • e
Transcription factors and intracellular receptors
(1) Basic domains
(1.1) Basic leucine zipper (bZIP) Activating transcription factor (1, 2, 3, 4, 5, 6) • AP-1 (c-Fos, FOSB, FOSL1, FOSL2, c-Jun, JUNB, JUND) • BACH (1, 2) • C/EBP (α, β, γ, δ, ε, ζ) • CREB (1, 3) • GABPA • MAF (B, F, G, K) • NRL • NRF1 • XBP1
(1.2) Basic helix-loop-helix (bHLH) ATOH1 • AhR • AHRR • ARNT • ASCL1 • BMAL (ARNTL, ARNTL2) • CLOCK • HIF (1A, 3A) • Myogenic regulatory factors (MyoD, Myogenin, MYF5, MYF6) • NEUROD1 • Twist • USF1
(1.3) bHLH-ZIP Myc • MITF • SREBP (1, 2)
(1.6) Basic helix-span-helix (bHSH) AP-2
(2) Zinc finger
DNA-binding domains
(2.1) Nuclear receptor (Cys4) subfamily 1 (Thyroid hormone (α, β), CAR, FXR, LXR (α, β), PPAR (α, β/δ, γ), PXR, RAR (α, β, γ), ROR (α, β, γ), Rev-ErbA (α, β), VDR) • subfamily 2 (COUP-TF (I, II), Ear-2, HNF4 (α, γ), PNR, RXR (α, β, γ), Testicular receptor (2, 4), TLX) • subfamily 3 (Steroid hormone (Estrogen (α, β), Estrogen related (α, β, γ), Androgen, Glucocorticoid, Mineralocorticoid, Progesterone)) • subfamily 4 NUR (NGFIB, NOR1, NURR1) • subfamily 5 (LRH-1, SF1) • subfamily 6 (GCNF) • subfamily 0 (DAX1, SHP)
(2.2) Other Cys4 GATA (1, 2, 3, 4, 5, 6)
(2.3) Cys2His2 General transcription factors (TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH: 1, 2) • GLI-Krüppel family (1, 2, 3, YY1) • KLF (2, 4, 5, 6, 10, 11, 12, 13) • Sp1 • zinc finger (3, 35, 43, 146, 148, 165, 217, 268, 281, 350) • Zbtb7 (7A) • ZBT (16, 17, 33)
(2.4) Cys6 HIVEP1
(3) Helix-turn-helix
domains
(3.1) Homeo domain ARX • Homeobox (A1, A3, A4, A5, A7, A9, A10, A11, A13, B1, B2, B3, B4, B5, B6, B7, B8, B9, B13, C4, C6, C8, C9, C13, D1, D3, D4, D9, D10, D11, D12, D13) • NANOG • NKX (2-1, 2-5, 3-1) • POU domain (PIT-1, BRN-3: 1, 2, Octamer transcription factor: 1, 2, 3/4, 6, 7)
(3.2) Paired box PAX (1, 2, 3, 4, 5, 6, 7, 8, 9)
(3.3) Fork head / winged helix E2F (1, 2, 3, 4, 5) • FOX proteins (C1, C2, E1, G1, H1, L2, M1, N3, O3, O4, P1, P2, P3)
(3.4) Heat Shock Factors HSF1
(3.5) Tryptophan clusters ELF (4, 5) • Interferon regulatory factors (1, 2, 3, 4, 5, 6, 7, 8) • MYB
(3.6) TEA domain transcriptional enhancer factor 1, 2
(4) β-Scaffold factors with
minor groove contacts
(4.1) Rel homology region NF-κB (NFKB1, NFKB2, REL, RELA, RELB) • NFAT (5, C1, C2, C3, C4)
(4.2) STAT STAT (1, 2, 3, 4, 5, 6)
(4.3) p53 p53
(4.4) MADS box Mef2 (A, B, C, D) • SRF
(4.7) High mobility group HNF (1A, 1B) • LEF1 • SOX (3, 4, 6, 9, 10, 13, 18) • SRY • SSRP1
(4.10) Cold-shock domain CSDA
(0) Other
transcription factors
(0.2) HMGI(Y) HMGA (1, 2)
(0.3) Pocket domain Rb • RBL1 • RBL2
(0.6) Miscellaneous ARID (1A, 1B, 2, 3A, 3B, 4A) • CAP • Rho/Sigma • R-SMAD
v • d • e
Tumor suppressor genes/proteins
APC - BRCA1 - BRCA2 - CHEK2 - Neurofibromin 1 - Maspin - Neurofibromin 2/Merlin - p14arf - p16 - p21 - p27 - p53 - p57 - p73 - pRb - PTEN - SDHB - SDHD - VHL
v • d • e
WikiDoc Research Resources for Retinoblastoma protein
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Evidence Based Medicine Regarding Retinoblastoma proteinCochrane Collaboration on Retinoblastoma protein • Bandolier on Retinoblastoma protein • TRIP on Retinoblastoma protein
Cost Effectiveness of Retinoblastoma proteinCost Effectiveness of Retinoblastoma protein
Clinical Trials Involving Retinoblastoma proteinOngoing Trials on Retinoblastoma protein at Clinical Trials.gov • Trial results on Retinoblastoma protein • Clinical Trials on Retinoblastoma protein at Google
Guidelines / Policies / Government Resources (FDA/CDC) Regarding Retinoblastoma proteinUS National Guidelines Clearinghouse on Retinoblastoma protein • NICE Guidance on Retinoblastoma protein • NHS PRODIGY Guidance • FDA on Retinoblastoma protein • CDC on Retinoblastoma protein
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Genetics, Pharmacogenomics, and Proteinomics of Retinoblastoma proteinGenetics of Retinoblastoma protein • Pharmacogenomics of Retinoblastoma protein • Proteomics of Retinoblastoma protein
Newstories on Retinoblastoma proteinRetinoblastoma protein in the news • Be alerted to news on Retinoblastoma protein • News trends on Retinoblastoma protein
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Informatics Resources on Retinoblastoma proteinList of terms related to Retinoblastoma protein
it:Proteina del retinoblastoma

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Acknowledgement and Attribution Regarding Sources of Content

Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .

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