Retinoblastoma protein

The Retinoblastoma protein, or pRb, is a tumor suppressorproteinfound to be dysfunctional in a number of types of cancer. pRb, also known as Rb, was so named because retinoblastomacancer results when the protein is inactivated by a mutation in both allelesof the gene that codes forit. The normal function of pRb is to prevent the cellfrom dividing or progressing through the cell cycle. Thus, when pRb is ineffective at this role, mutatedcells 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 (Korenjak and Brehm, 2005; Münger and Howley, 2002). Oncogenicproteins such as those produced by cells infected by high-risk types of human papillomavirusescan bind and inactivate pRb, which can lead to cancer.

Cell cycle supression

pRb prevents the cell from replicating damaged DNA by preventing its progression through the cell cycle into its S, or synthesis phaseor progressing through G1, or first gap phase(Das et al., 2005). pRb binds and inhibits a transcription factorcalled E2 promoter-binding?protein-dimerization partner(E2F-DP), which is needed to push the cell into S phase (Funk et al., 1997; De Veylder et al., 2003; de Jager et al., 2005; Greenblatt, 2005; Sinal and Woods, 2005). 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 (Münger and Howley, 2002). The pRb-E2F/DP complex also attracts a protein called histone deacetylaseto the chromatin, further supressing DNA synthesis.

Activation and inactivation

pRb is active when it is dephosphorylatedand inactivated when it is phosphorylated. It is activated near the end of mitosis(M phase) when a phosphatasedephosphorylates it, allowing it to bind E2F (Münger and Howley, 2002).

When it is time to enter S phase, complexes of a cyclin-dependent kinases(CDK) and cyclinsphosphorylate pRb, inhibiting its activity (Münger and Howley, 2002; Bartkova et al, 2003; Das et al., 2005; Korenjak and Brehm, 2005). The initial phosphorylation is performed by Cyclin D/CDK4,6 and the later by Cyclin E/CDK2. It remains phosphorylated throughout S, G2 and M phases (Münger and Howley, 2002).

Inhibiting Rb allows E2F-DP to dissociate from the complex and become active (Münger and Howley, 2002; De Veylder et al., 2003; Das et al., 2005). 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 repairby helping to attach polymerasesto DNA (Funk et al., 1997; Das et al., 2005; Greenblatt, 2005).

References

• 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.
• 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.
• 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.
• De Veylder L., Joubès J., and Inzé D. 2003. Plant cell cycle transitions. Current Opinion in Plant Biology. 6(6): 536-543.
• 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.
• Greenblatt R.J. 2005. Human papillomaviruses: Diseases, diagnosis, and a possible vaccine. Clinical Microbiology Newsletter, 27(18), 139-145.
• 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.
• Münger, K. and Howley, P.M., 2002. Human papillomavirus immortalization and transformation functions. Virus Research, 89: 213?228.
• 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.

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It uses material from the http://en.wikipedia.org/wiki/Retinoblastoma+protein Wikipedia article Retinoblastoma protein.