Retinoblastoma protein
From Wikipedia, the free encyclopedia
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retinoblastoma 1 (including osteosarcoma)
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| Identifiers | |
| Symbol | RB1 OSRC |
| HUGO | 9884 |
| Entrez | 5925 |
| OMIM | 180200 |
| RefSeq | NM_000321 |
| UniProt | P06400 |
| Other data | |
| Locus | Chr. 13 q14.2 |
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 is there because the retinoblastoma protein is usually present as a phosphoprotein inside cells. pRb 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.
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[edit] 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 protein called histone deacetylase (HDAC) to the chromatin, further suppressing DNA synthesis.
[edit] 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 mitosis (M 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]
[edit] See also
- p53 - involved in the DNA repair support function of pRb
There is a diagram of these interactions here.
[edit] References
- ^ 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.
- ^ a b 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.
- ^ a b c d e f Münger K. and Howley P.M. 2002. Human papillomavirus immortalization and transformation functions. Virus Research, 89: 213–228.
- ^ a b c d 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.
- ^ 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.
- ^ a b 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.
- ^ a b De Veylder L., Joubès J., and Inzé D. 2003. Plant cell cycle transitions. Current Opinion in Plant Biology. 6(6): 536-543.
- ^ 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.
- ^ a b 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.
- ^ 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.
- ^ 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.
- ^ 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.
