p53 mutation heterogeneity in cancer
ABSTRACT The p53 gene is inactivated in about 50% of human cancers and the p53 protein is an essential component of the cell response induced by genotoxic stresses such as those generated by radiotherapy or chemotherapy. It is therefore highly likely that these alterations are an important component in tumor resistance to therapy. The particular characteristics of these alterations, 80% of which are missense mutations leading to functionally heterogeneous proteins, make p53 a unique gene in the class of tumor suppressor genes. A considerable number of mutant p53 proteins probably have an oncogenic activity per se and therefore actively participate in cell transformation. The fact that the apoptotic and antiproliferative functions of p53 can be dissociated in certain mutants also suggests another level of complexity in the relationships between p53 inactivation and neoplasia.
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ABSTRACT: p53 Tumor suppressor gene encodes for a critical cellular protein that regulates the integrity of the cell and can induce cell cycle arrest and/or apoptosis upon cellular stresses of several origins, including chemotherapeutics. Loss of p53 function occurs in an estimated 50% of all cancers by mutations and deletions while in the presence of wild-type p53 alleles other mechanisms may affect the expression and activity of p53. Alternate mechanisms include methylation of the promoter of p53, deletion or epigenetic inactivation of the p53-positive regulator p14/ARF, elevated expression of the p53 regulators murine double minute 2 (MDM2) and MDMX, or alteration of upstream regulators of p53 such as the kinase ATM. MDM2 is a p53 E3 ubiquitin ligase that mediates the ubiquitin-dependent degradation of p53 while p14/ARF is a small MDM2-binding protein that controls the activity of MDM2 by displacing p53 and preventing its degradation. MDMX antagonize p53-dependent transcriptional control by interfering with p53 transactivation function. The understanding of the key role of p53 inactivation in cancer development generated considerable interest in developing compounds that are capable of restoring the p53 functions. Several patents have been issued on such compounds. Adenovirus-based p53 gene therapy as well as small molecules such as PRIMA that can restore the transcriptional transactivation function to mutant p53, or NUTLIN and RITA that interfere with MDM2-directed p53 degradation, have tested in a preclinical setting and some of these approaches are currently in clinical development.Topics in Anti-Cancer Research, Edited by Atta-ur-Rahman and Khurshid Zaman, 01/2012: chapter 1978-1-60805-612-5: pages 192-227; BENTHAM SCIENCE., ISBN: 978-1-60805-612-5
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ABSTRACT: The aim of the present study was to determine whether endothelial nitric oxide synthase (eNOS) gene polymorphisms play a role in development of bladder cancer in the Turkish population. The study was performed on 75 patients (64 men, 11 women) with bladder cancer and 143 healthy individuals (107 men, 36 women) with any kind of cancer history. Three eNOS gene polymorphisms (T-786C promoter region, G894T and intron 4 VNTR 4a/b) were determined with polymerase chain reaction and restriction fragment lenght polymorphism methods. In our study, GT and TT genotypes for eNOS G894T polymorphism were found to significantly vary among patients with bladder cancer and control group (OR: 0.185, CI: 0.078-0.439, p=0.0001 and OR: 0.324, CI: 0.106-0.990, p=0.026). Also, the frequency of the 894T allele was significantly higher in patients with bladder cancer (51%). No association was identified for eNOS T-786C and intron 4 VNTR 4a/b polymorphisms between patients with bladder cancer and control groups in our Turkish population.