The p53 tumor suppressor gene (TP53) is mutated more often in human cancers than any other gene yet reported. Of importance, it is mutated frequently in the common human malignancies of the breast and colorectum and also, but less frequently, in other significant human cancers such as glioblastomas. There is also one inherited cancer predisposing syndrome called Li-Fraumeni that is caused by TP53 mutations. In this review, we discuss the significance of p53 mutations in some of the above tumors with a view to outlining how p53 contributes to malignant progression. We also discuss the usefulness of TP53 status as a prognostic marker and its role as a predictor of response to therapy. Finally, we outline some evidence that abnormalities in p53 function contribute to the etiology of other non-neoplastic diseases.
"At normal circumstances, P 53 expression is low because of its limited needs which result in its speed inactivation but it has an ability to be more stable, active and accumulative in response to activator signals such as DNA destruction, then its transcriptive and expression level increase leading to disturbance in the cell cycle which revealed the apoptotic features (Naderi et al., 2009). P 53 prevents tumor evolution and progression and activates death of cells subjected to anti-tumor therapy which made P 53 as ''guardian angel'' as described by Royds and Iacopetta, 2006. In addition to P 53 , caspases in general are important mediators in apoptosis, executive cas- pase-3 is the most involved pathway which should be generated from its inactive protein (procaspase-3), caspase 3 is required for some apoptosis features (chromatin condensation, DNA damage and apoptotic body formation) and its role may take place before cell viability suppression starts (Porter and Ja¨nicke (1999). "
[Show abstract][Hide abstract] ABSTRACT: Apoptosis is a significant physiological function in the cell. P53 is known as tumor suppressor cellular factor, executive caspases are also the most involved pathway for apoptosis. Menadione (VK3) has apoptotic action on many harmful cells, but the molecular role of adipokines is not enough studied in this regard, so the ability of menadione to modify the adipokine (leptin hormone), caspase-3 and P53 signals to induce its apoptotic action on HepG2 cells was studied. The study revealed that menadione has anti-viability and apoptotic effect at sub-G1 phase of HepG2 cell cycle. Its cytotoxic effect is mediated by molecular mechanisms included: inhibiting leptin expression and level, activating caspase-3 pathway and up-regulating the expression of P53. Menadione exerts its apoptotic mechanisms in a concentration and time dependent way through ROS generation. In addition to the known apoptotic pathways, the results indicates that suppressing leptin pathway is a significant mechanism for menadione apoptotic effect which made it as potential therapeutic vitamin in preventing hepatocytes survival and proliferation.
Saudi Journal of Biological Sciences 03/2014; 21(6). DOI:10.1016/j.sjbs.2014.03.002 · 1.26 Impact Factor
"The complex repertoire of p53- regulated genes further highlights the imperative need to understand how p53 selects its key target genes. Mutation of p53 is a common occurrence in many cancers and is associated with tumor progression, resistance to chemotherapy, and poor prognosis . A study of breast cancers found that p53 mutation frequency was not related to nodal involvement or tumor size , although another study found a marginally increased frequency in recurrent tumors . "
[Show abstract][Hide abstract] ABSTRACT: In breast carcinoma, disruption of the p53 pathway is one of the most common genetic alterations. The observation that the p53 can express multiple protein isoforms adds a novel level of complexity to the outcome of p53 mutations. p53 expression was analysed by Western immunoblotting and immunohistochemistry using monoclonal antibodies DO-7, Pab240, and polyclonal antiserum CM-1. The more frequently p53-positive nuclear staining has been found in the invasive breast tumors. One of the most intriguing findings is that mutant p53 appears as discrete dot-shaped regions within the nucleus of breast cancer cells. In many malignant cells, the nucleolar sequestration of p53 is evident. These observations support the view that the nucleolus is involved directly in the mediation of p53 function or indirectly by the control of the localization of p53 interplayers. p53 expressed in the nuclear fraction of breast cancer cells revealed a wide spectrum of isoforms. p53 isoforms ΔNp53 (47 kDa) and Δ133p53
(35 kDa), known as dominant-negative repressors of p53 function, were detected as the most predominant variants in nuclei of invasive breast carcinoma cells. The isoforms expressed also varied between individual tumors, indicating potential roles of these p53 variants in human breast cancer.
The Scientific World Journal 01/2014; 2014(22):618698. DOI:10.1155/2014/618698 · 1.73 Impact Factor
"Upon treatment with DNA methylation inhibitors, tumor suppressor genes are activated, which then lead to cell cycle arrest or apoptosis. p53 is one of the best characterized tumor suppressor gene, mutated in up to 50% of cancers (Royds and Iacopetta 2006). p53 can be activated by various signals, such as irradiation or chemical induced DNA damage, abnormal oncogene expression, microtubule inhibitors and other stress conditions (Royds and Iacopetta 2006; Kruse and Gu 2009). "
[Show abstract][Hide abstract] ABSTRACT: Multiple epigenetic changes, including alterations in DNA methylation occur during tumorigenesis. Various inhibitors of DNA methylation have been developed to prevent proliferation of cancer cells. 5-fluoro-2′-deoxycytidine (FCdR) is one such DNA methylation inhibitor, which is currently in phase II clinical trial. To investigate the molecular mechanism/s by which FCdR might mediate repression of tumor cell proliferation, we analyzed the toxicity of FCdR in various cell lines established from different sarcomas. We found HCT116, a colon cancer cell line, is much more sensitive to FCdR compared to others. FCdR treatment inhibited HCT116 cells at G2/M check point and up-regulated expression of multiple cancer-related genes, which could be due to its inhibitory activity towards DNA methylation. Furthermore, we found that FCdR activates DNA damage response pathway. Using an inhibitor for ATM and ATR kinases activity, which are required for amplifying the DNA damage repair signal, we show that FCdR induced inhibition of HCT116 cells at G2/M is mediated through activation of DNA damage response pathway.
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