- Retinoblastoma protein
The retinoblastoma protein (abbreviated pRb or "Rb") is a
tumor suppressor proteinthat is dysfunctional in many types of cancer.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.] One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycleprogression until a cell is ready to divide.
pRb belongs to the
pocket protein family, whose members have a pocket for the functional binding of other proteins.Korenjak M. and Brehm A. 2005. [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VS0-4GSJXD8-1&_coverDate=10%2F31%2F2005&_alid=324524977&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=6248&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=433dbaa00425e7b5ca02f73279fbc321 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. [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T32-46W13SB-2&_coverDate=11%2F30%2F2002&_alid=324525784&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4934&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=e7d4057a8f6b3c57fee07e374e77fd5d Human papillomavirus immortalization and transformation functions] . "Virus Research", 89: 213–228. ] Should an oncogenicprotein, such as those produced by cells infected by high-risk types of human papillomaviruses, bind and inactivate pRb, this can lead to cancer.
Name and genetics
In humans, the protein is encoded by the
RB1gene located on 13q14.1-q14.2. If both alleles of this gene are mutated early in life, the protein is inactivated and results in development of retinoblastomacancer, hence the name "Rb". It is not known why an eye cancer results from a mutation in a gene that is important all over the body.
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 ["J Clin Oncol" (2005) 23:2272] . 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 pRb 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 [Knudson 1971, "Proc Acad Nat Sci USA" 68:820] . The working allele need not undergo a mutation "per se", as loss of heterozygosityis 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
polynomialkinetics, not exactly quadraticas expected because the first mutation must arise through normal mechanisms, and then can be duplicated by LOH to result in a tumour progenitor.
Cell cycle suppression
pRb prevents the cell from replicating damaged DNA by preventing its progression along the cell cycle through G1 (
first gap phase) into S ( synthesis phase).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.] pRb binds and inhibits transcription factors of the E2Ffamily, which are composed of dimers of an E2F protein and a DP protein. Wu C.L., Zukerberg L.R., Ngwu C., Harlow E. and Lees J.A. 1995. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=7739537 "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.] The transcription activating complexes of E2 promoter-binding–protein-dimerization partners (E2F-DP) can push a cell into S phase.Funk J.O., Waga S., Harry J.B., Espling E., Stillman B., and Galloway D.A. 1997. [http://www.genesdev.org/cgi/content/full/11/16/2090 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.] De Veylder L., Joubès J., and Inzé D. 2003. [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VS4-49KH3G2-1&_coverDate=12%2F31%2F2003&_alid=324521740&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=6252&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=40e5304bd36a43ee0f9ef82ab574339d 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. [http://www.biot.cam.ac.uk/jahm/pdf_files/SCDB385.pdf 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.] Greenblatt R.J. 2005. [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T5D-4H6P7Y9-1&_user=10&_handle=V-WA-A-W-W-MsSAYZA-UUA-U-AABAVZDCWU-AAWEUVYBWU-BEAYVEYEY-W-U&_fmt=summary&_coverDate=09%2F15%2F2005&_rdoc=1&_orig=browse&_srch=%23toc%235000%232005%23999729981%23607092!&_cdi=5000&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=42b5289fd6b206fd7ae9269741210c39 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. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16210110&query_hl=8 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.] 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. The pRb-E2F/DP complex also attracts a histone deacetylase(HDAC) protein to the chromatin, further suppressing DNA synthesis.
Activation and inactivation
In the hypophosphorylated state, pRb is active and carries out its role as tumor suppressor by inhibiting cell cycle progression. Phosphorylation inactivates pRb. During the M-to-G1 transition, pRb is progressively dephosphorylated by PP1, returning to its growth-suppressive hypophosphorylated state .Vietri M., Bianchi M., Ludlow J.W., Mittnacht S. and Villa-Moruzzi E. 2006. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16466572 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.]
When it is time for a cell to enter S phase, complexes of
cyclin-dependent kinases (CDK) and cyclins phosphorylate pRb, inhibiting its activity.Bartkova J., Grøn B., Dabelsteen E., and Bartek J. 2003. [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T4J-481FJ6W-4&_coverDate=02%2F28%2F2003&_alid=324520285&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4976&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=cefdf7198634e1b85780e1e5bb17bd00 Cell-cycle regulatory proteins in human wound healing] . "Archives of Oral Biology", 48(2): 125-132. PMID 12642231. Retrieved on January 24, 2007.] 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.
Phosphorylation of pRb allows E2F-DP to dissociate from pRb and become active. 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.
p53- involved in the DNA repair support function of pRb
*cite journal | author=Momand J, Wu HH, Dasgupta G |title=MDM2--master regulator of the p53 tumor suppressor protein. |journal=Gene |volume=242 |issue= 1-2 |pages= 15–29 |year= 2000 |pmid= 10721693 |doi=
*cite journal | author=Zheng L, Lee WH |title=Retinoblastoma tumor suppressor and genome stability. |journal=Adv. Cancer Res. |volume=85 |issue= |pages= 13–50 |year= 2003 |pmid= 12374284 |doi=
*cite journal | author=Classon M, Harlow E |title=The retinoblastoma tumour suppressor in development and cancer. |journal=Nat. Rev. Cancer |volume=2 |issue= 12 |pages= 910–7 |year= 2003 |pmid= 12459729 |doi= 10.1038/nrc950
*cite journal | author=Lai H, Ma F, Lai S |title=Identification of the novel role of pRB in eye cancer. |journal=J. Cell. Biochem. |volume=88 |issue= 1 |pages= 121–7 |year= 2003 |pmid= 12461781 |doi= 10.1002/jcb.10283
*cite journal | author=Simin K, Wu H, Lu L, "et al." |title=pRb inactivation in mammary cells reveals common mechanisms for tumor initiation and progression in divergent epithelia. |journal=PLoS Biol. |volume=2 |issue= 2 |pages= E22 |year= 2006 |pmid= 14966529 |doi= 10.1371/journal.pbio.0020022
*cite journal | author=Lohmann DR, Gallie BL |title=Retinoblastoma: revisiting the model prototype of inherited cancer. |journal=American journal of medical genetics. Part C, Seminars in medical genetics |volume=129 |issue= 1 |pages= 23–8 |year= 2004 |pmid= 15264269 |doi= 10.1002/ajmg.c.30024
*cite journal | author=Clemo NK, Arhel NJ, Barnes JD, "et al." |title=The role of the retinoblastoma protein (Rb) in the nuclear localization of BAG-1: implications for colorectal tumour cell survival. |journal=Biochem. Soc. Trans. |volume=33 |issue= Pt 4 |pages= 676–8 |year= 2005 |pmid= 16042572 |doi= 10.1042/BST0330676
*cite journal | author=Rodríguez-Cruz M, del Prado M, Salcedo M |title= [Genomic retinoblastoma perspectives: implications of tumor supressor gene RB1] |journal=Rev. Invest. Clin. |volume=57 |issue= 4 |pages= 572–81 |year= 2006 |pmid= 16315642 |doi=
*cite journal | author=Knudsen ES, Knudsen KE |title=Retinoblastoma tumor suppressor: where cancer meets the cell cycle. |journal=Exp. Biol. Med. (Maywood) |volume=231 |issue= 7 |pages= 1271–81 |year= 2006 |pmid= 16816134 |doi=
* [http://rb1-lsdb.d-lohmann.de/ Retinoblastoma Genetics]
* There is a diagram of the pRb-E2F interactions [http://courses.biology.utah.edu/golic/2030/Cell%20cycle:cancer/cyclin:cdk%20control.jpghere] .
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