Role of the retinoblastoma protein in the pathogenesis of human cancer

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 12/1997; 15(11):3301-12.
Source: PubMed

ABSTRACT The retinoblastoma gene (RB-1) was originally identified as the gene involved in hereditary retinoblastoma. However, RB-1 mutations are found in a number of common mesenchymal and epithelial malignancies. The retinoblastoma protein (pRB) acts as a transcriptional regulator of genes involved in DNA synthesis and cell-cycle control. In this regard, the functional interaction between pRB and the E2F transcription factor family appears to be critical. The pRB-E2F interaction is, in turn, regulated by a pathway that includes cyclin D1, cdk4, and p16. Mutations that affect this pathway have been documented in nearly every type of adult cancer. Thus, perturbation of pRB function may be required for the development of cancer. Insights into the biochemical functions of pRB, and its upstream regulators, may form the basis for the development of novel antineoplastic agents.

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    • "However, Rb1 gene mutations are only found in small subsets of human tumors. This indicates that, as the functional inactivation of pRb probably also affects the other Rb family members p107 and p130, the specific inactivation of Rb1 gene is only able to induce tumorigenesis in restricted tissues3536. In epidermis, although Rb1 loss promotes alterations in proliferation and differentiation, indicating the existence of unique functions for this protein in this tissue, it is insufficient to allow tumor development6. "
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    ABSTRACT: The specific ablation of Rb1 gene in stratified epithelia (Rb(F/F);K14cre) promotes proliferation and altered differentiation but is insufficient to produce spontaneous tumors. The pRb relative, p107, compensates some of the functions of pRb in these tissues; however, Rb(F/F);K14cre;p107(-/-) mice die postnatally. Here we show, using an inducible mouse model (Rb(F/F);K14creER(TM)), that p107 exerts specific tumor suppressor functions in the absence of pRb in stratified epithelia. The simultaneous absence of pRb and p107 produces impaired p53 transcriptional functions and reduction of Pten expression, allowing spontaneous squamous carcinoma development. These tumors display significant overlap with human squamous carcinomas, supporting that Rb(F/F);K14creER(TM);p107(-/-) mice might constitute a new model for these malignancies. Remarkably tumor development in vivo is partially alleviated by mTOR inhibition. These data demonstrate the existence of a previously unreported functional connection between pRb, Pten and p53 tumor suppressors, through p107, of a particular relevance in squamous tumor development.
    Scientific Reports 11/2012; 2:828. DOI:10.1038/srep00828 · 5.58 Impact Factor
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    • "As cells progress into S phase, maintenance of RB hyperphosphorylation is necessary for the successful completion of DNA replication [33]. Mu-tations that affect the RB signaling pathway have been iden-tified in the majority of human cancers [34]. CDKs are also regulated by a group of functionally related proteins called CDK inhibitors. "
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    ABSTRACT: The cell cycle is the cascade of events that allows a growing cell to duplicate all its components and split into two daughter cells. Cell cycle progression is mediated by the activation of a highly conserved family of protein kinases, the cyclin-dependent kinases (CDKs). CDKs are also regulated by related proteins called cdk inhibitors grouped into two families: the INK4 inhibitors (p16, p15, p19, and p18) and the Cip/Kip inhibitors (p21, p27, and p53). Several studies report the importance of cell-cycle proteins in the pathogenesis and the prognosis of lung cancer. This paper will review the most recent data from the literature about the regulation of cell cycle. Finally, based essentially on the data generated in our laboratory, the expression, the diagnostic, and prognostic significance of cell-cycle molecules in lung cancer will be examined.
    Pathology Research International 10/2011; 2011:605042. DOI:10.4061/2011/605042
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    • "Oncogenic proteins, such as those produced by virus-infected cells, can bind and inactivate pRb, eventually leading to tumorogenesis. Accordingly, in a number of cancer types, pRb was found to be dysfunctional (Das et al. 2005; Funk et al. 1997; Ludlow and Skuse 1995; Nevins 2001; Sellers and Kaelin 1997). RBRs are also involved in DNA repair, DNA damage checkpoint control, differentiation, cellular senescence, and apoptosis. "
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    ABSTRACT: The retinoblastoma tumor suppressor protein (pRb) regulates cell cycle progression by controlling the G1-to-S phase transition. As evidenced in mammals, pRb has three functionally distinct binding domains and interacts with a number of proteins including the E2F family of transcription factors, proteins with a conserved LxCxE motif (D-type cyclin), and c-Abl tyrosine kinase. CDK-mediated phosphorylation of pRb inhibits its ability to bind target proteins, thus enabling further progression of the cell cycle. As yet, the roles of pRb and pRb-binding factors have not been well characterized in plants. By using antibody which specifically recognizes phosphorylated serines (S807/811) in the c-Abl tyrosine kinase binding C-domain of human pRb, we provide evidence for the cell cycle-dependent changes in pRb-like proteins in root meristems cells of Vicia faba. An increased phosphorylation of this protein has been found correlated with the G1-to-S phase transition.
    Protoplasma 03/2011; 249(1):131-7. DOI:10.1007/s00709-011-0272-7 · 2.65 Impact Factor
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