RB is the Retinoblastoma gene, which codes for a protein (pRb) that functions in regulation of cell cycle progression. Rb, together with p107 (RBL1) and Rb2/p130 (RBL2), is a member of the pocket protein (PP) family, which share a 'pocket' domain responsible for most of the functional interactions characterizing the activity of this family of cellular factors. Pocket proteins play crucial roles in the metazoan cell cycle through interaction with members of the E2F family of transcription factors. The pocket proteins regulate apoptosis, the cell cycle, and tissue-specific gene expression.
The pRb protein's ability to regulate the cell cycle correlates to its phosphorylation state. Phosphorylation is maximal at the start of S phase and minimal after mitosis and entry into G1. Mitogen stimulation of quiescent cells induces phosphorylation of pRB, while in contrast, differentiation induces hypophosphorylation of pRB. Therefore, the hypophosphorylated form of pRB suppresses cell proliferation.
pRb is one of the most significant substrates for phosphorylation by the G1 cyclin-CDK complexes that regulate progression through the cell cycle. As a pocket protein, pRB forms a complex with the E2F family of transcription factors. The formation of the complex inactivates E2F. Phosporylation of pRb by the G1 cyclin-CDK complex (cyclin D-CDK4/6 complex) causes pRb release from the pRb-E2F complex, freeing E2F to transcriptionally activate genes. Within the cell cycle, E2F increases the transcription of the S-phase cyclins as well as leads to increases in its' own transcription.
The c-MYC gene is an element in the growth suppressive pathway of pRB. Suppression of c-MYC expression accompanies proliferation of keratinocytes by TGF-β. Inhibition of c-MYC expression can be abrogated by introduction of vectors that express the SV40 and adenovirus large T antigens that bind pRb. Therefore, there is a link between TGF-β, pRB and c-MYC expression in keratinocytes.
Binding by hypophoshorylated pRb, which inhibits proliferation, to the transforming proteins of the DNA tumor viruses, adenovirus, SV40, polyoma, HPV, and BK accomplishes transformation of the viruses.
Various mutations result in loss of Rb function, and 30% of retinoblastomas contain large scale deletions. Splicing errors, point mutations and small deletions in the promoter regions have also been observed in some retinoblastomas.
Retinoblastoma family proteins as key targets of the small DNA virus oncoproteins.
RB, the most investigated tumor suppressor gene, is the founder of the RB family of growth/tumor suppressors, which comprises also p107 (RBL1) and Rb2/p130 (RBL2). The protein products of these genes, pRb, p107 and pRb2/p130, respectively, are also known as 'pocket proteins', because they share a 'pocket' domain responsible for most of the functional interactions characterizing the activity of this family of cellular factors. The interest in these genes and proteins springs essentially from their ability to regulate negatively cell cycle processes and for their ability to slow down or abrogate neoplastic growth. The pocket domain of the RB family proteins is dramatically hampered in its functions by the interference of a number of proteins produced by the small DNA viruses. In the last two decades, the 'viral hypothesis' of cancer has received a considerable renewed impulse from the notion that small DNA viruses, such as Adenovirus, Human papillomavirus (HPV) and Polyomavirus, produce factors that can physically interact with major cellular regulators and alter their function. These viral proteins (oncoproteins) act as multifaceted molecular devices that have evolved to perform very specific tasks. Owing to these features, viral oncoproteins have been widely employed as invaluable experimental tools for the identification of several key families of regulators, particularly of the cell cycle homeostasis. Adenovirus early-region 1A (E1A) is the most widely investigated small DNA tumor virus oncoprotein, but relevant interest in human oncology is raised by the E1A-related E7 protein from transforming HPV strains and by Polyomavirus oncoproteins, particularly large and small T antigens from Simian virus 40, JC virus and BK virus. Felsani A,
Mileo AM, Paggi MG. Retinoblastoma family proteins as key targets of the small DNA virus oncoproteins. Oncogene. 2006 Aug 28;25(38):5277-85.
DNA tumor virus oncoproteins and retinoblastoma gene mutations share the ability to relieve the cell's requirement for cyclin D1 function in G1. [J Cell Biol. 1994] PMID: 8175885
Protein expression of the RB-related gene family and SV40 large T antigen in mesothelioma and lung cancer. [Oncogene. 2000] PMID: 11030152
Mechanisms by which DNA tumor virus oncoproteins target the Rb family of pocket proteins. [Carcinogenesis. 2003] PMID: 12584163
Retinoblastoma protein family in cell cycle and cancer: a review. [J Cell Biochem. 1996] PMID: 8872613
Role of the interaction between large T antigen and Rb family members in the oncogenicity of JC virus. [Oncogene. 2006] PMID: 16936750
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