Role of the retinoblastoma protein in the pathogenesis of human cancer.
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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ABSTRACT: Recent evidence indicates a potential prognostic and predictive value for germline polymorphisms in genes involved in cell cycle control. We investigated the effect of cyclin D1 (CCND1) rs9344 G>A in stage II/III colon cancer patients and validated the findings in an independent study cohort. For evaluation and validation set, a total of 264 and 234 patients were included. Patients treated with 5-fluorouracil-based chemotherapy, carrying the CCND1 rs9344 A/A genotype had significantly decreased time-to-tumor recurrence (TTR) in univariate analysis and multivariate analysis (hazard ratio (HR) 2.47; 95% confidence interval (CI) 1.16-5.29; P=0.019). There was no significant association between CCND1 rs9344 G>A and TTR in patients with curative surgery alone. In the validation set, the A allele of CCND1 rs9344 G>A remained significantly associated with decreased TTR in univariate and multivariate analyses (HR 1.94; 95% CI 1.05-3.58; P=0.035). CCND1 rs9344 G>A may be a predictive and/or prognostic biomarker in stage II/III colon cancer patients, however, prospective trials are warranted to confirm our findings.The Pharmacogenomics Journal advance online publication, 9 April 2013; doi:10.1038/tpj.2013.15.The Pharmacogenomics Journal 04/2013; · 5.13 Impact Factor
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ABSTRACT: Transcription factor E2F-1 and its interaction with pRb provide a key point of control in cell proliferation. E2F-1 participates in both cell cycle progression and apoptosis, and in cells exists with a DP dimerization partner protein, the most prominent being DP-1. By mining the tumor tissue and cancer cell line encyclopedia genomic databases, we identified the first somatic mutations in the DP-1 gene and describe 53 distinct mutation events here. The mutations are mostly missense mutations, but also include nonsense and frame-shift mutations that result in truncated DP-1 derivatives. Mutation occurs throughout the DP-1 gene but generally leaves protein dimerization activity intact. This allows the mutant derivatives to affect the properties of the E2F-1/DP-1 heterodimer through a transdominant mechanism, which changes the DNA binding, transcriptional activation and pRb-binding properties of the heterodimer. In particular, many DP-1 mutants were found to impair E2F-1-dependent apoptosis. Our results establish that somatic mutations in DP-1 uncouple normal control of the E2F pathway, and thus define a new mechanism that could contribute to aberrant proliferation in tumor cells.Oncogene advance online publication, 12 August 2013; doi:10.1038/onc.2013.316.Oncogene 08/2013; · 8.56 Impact Factor
- Journal of the Pakistan Medical Association 10/2013; · 0.41 Impact Factor