The Importance Of The TP53 Gene

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Arguably, the most famous gene in the human genome, the TP53 gene, can be found on chromosome 17p13.1. This gene encodes the p53 tumor suppressor protein, which happens to be the most frequently mutated protein in human cancer, with greater than half of all tumors harboring mutations at this locus (Vogelsteinet al. 2000; Petitjean et al. 2007b). In its controversial discovery, the p53 protein was first identified as an oncogene because of its association with the simian virus 40 (SV40) large T-antigen (Lane and Crawford 1979; Linzer and Levine 1979). Subsequently, it was observed that many tumors express this protein in excess quantities, suggesting once more that p53 might act as a cellular oncogene (DeLeo et al. 1979; Rotter 1983). This notion was reinforced when investigators, Eliyahu et al. and Parada et al., ectopically expressed the newly cloned p53 cDNAs into primary cells. The expression with p53 cooperated in conjunction with oncogenic Ras to transform primary cells in culture. Likewise, Wolf and colleagues overexpressed p53 in cells where endogenous p53 had been inactivated by retroviral insertions and demonstrated an increase in tumorigenicity. Thus, with a wealth of supporting evidence and papers published in top quality journals, all attesting to p53’s oncogenic characteristics, who would doubt them?
Several scientists did. Contradictions were raised when a group of investigators were having trouble replicating the newly published results describing oncogenic p53 particularly, in regards to its ability to transform primary cells. Interestingly, when several groups compared their cloned p53 cDNA sequences with each other, none where identical (Levine and Oren 2009). As a result, it has become widely acknowledged that t...

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MDM2 functions to keep p53 levels in check during unstressed cellular conditions. However, p53 is stabilized in response to a wide variety of cellular stresses including DNA damage, Radioactive Oxygen Species, hypoxia, oncogene activation, osmotic shock and even ribonucleotide depletion (Vousden and Lu 2002; Han et al. 2008). This stabilization and activation of p53 in response to stress is mediated through many post-translational modifications targeting various domains. The p53 protein is composed of an acidic N-terminal transactivation domain, a proline-rich domain, a DNA-binding domain, an oligomerization domain and a basic C-terminal regulatory domain (Laptenko and Prives 2006). The N-terminus of p53 is heavily phosphorylated in response to DNA damage, whereas the C-terminus may be phosphorylated, acetylated, neddylated, ubiquitinated or sumoylated.
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