Role of Rb 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


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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    • "Although the two-hit hypothesis suggested that the first few years following birth reflects the time-interval for homozygous RB1 mutation, a large number of cytogenetic and comparative genomic hybridization studies have shown that RB1 inactivation is not sufficient for determining retinoblastoma. These studies have suggested that mutations of both alleles of the RB1 gene are necessary for retinoblastoma tumor initiation (Wang et al., 1994) but not sufficient for malignant transformation (Sellers and Kaelin, 1997). Thus, additional mutational events (three hits) are required for RB1À/À cells to progress into a fully malignant tumor (Corson and Gallie, 2007). "
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    ABSTRACT: Loss of RB1 gene is considered either a causal or an accelerating event in retinoblastoma. A variety of mechanisms inactivates RB1 gene, including intragenic mutations, loss of expression by methylation and chromosomal deletions, with effects which are species- and cell type- specific. RB1 deletion can even lead to aneuploidy thus greatly increasing cancer risk. The RB1gene is part of a larger gene family that includes RBL1 and RBL2, each of the three encoding structurally related proteins indicated as pRb, p107 and p130, respectively. The great interest in these genes and proteins springs from their ability to slow down neoplastic growth. pRb can associate with various proteins by which it can regulate a great number of cellular activities. In particular, its association with the E2F transcription factor family allows the control of the main pRb functions, while the loss of these interactions greatly enhances cancer development. As RB1 gene, also pRb can be functionally inactivated through disparate mechanisms which are often tissue specific and dependent on the scenario of the involved tumor suppressors and oncogenes. The critical role of the context is complicated by the different functions played by the RB proteins and the E2F family members. In this review, we want to emphasize the importance of the mechanisms of RB1/pRb inactivation in inducing cancer cell development. The review is divided in three chapters describing in succession the mechanisms of RB1 inactivation in cancer cells, the alterations of pRb pathway in tumorigenesis and the RB protein and E2F family in cancer. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 08/2013; 228(8). DOI:10.1002/jcp.24329 · 3.84 Impact Factor
    • "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(12):605042. DOI:10.4061/2011/605042
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