Retinoblastoma protein

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The retinoblastoma protein (pRb) is a tumor suppressor protein found to be dysfunctional in a number of types of cancer^[1]. pRb, also known as Rb, 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. RB is a target for phosphorylation by several kinases as described below. The normal 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 (Korenjak and Brehm, 2005; Münger and Howley, 2002). 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.

Contents 1 Cell cycle supression 2 Activation and inactivation 3 See also 4 References

[edit] Cell cycle supression

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 (Das et al., 2005). pRb binds and inhibits transcription factors of the E2F family. E2F transcription factors are dimers of an E2F protein and a DP protein ^[2]. The transcription activating complexes of E2 promoter-binding–protein-dimerization partners (E2F-DP) can push a 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 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] (Münger and Howley, 2002).

When it is time for a cell to enter S phase, complexes of cyclin-dependent kinases (CDK) and cyclins, phosphorylate 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 followed by additional phosphorylation by Cyclin E/CDK2. pRb remains phosphorylated throughout S, G2 and M phases (Münger and Howley, 2002).

Phosphorylation of pRb allows E2F-DP to dissociate from pRb 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 repair by helping to attach polymerase to DNA (Funk et al., 1997; Das et al., 2005; Greenblatt, 2005).

[edit] See also

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

There is a diagram of these interactions here

[edit] 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.