Pillai, M R and S., Asha Nair (2016) Polymorphism of p53 in cancer prognosis. The Indian journal of medical research, 144 (3). pp. 314-316. ISSN 0971-5916

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Abstract

Oncogenic activity or loss of tumour suppressor function results from genetic alterations within tumour cells, which finally leads to abnormal gene expression. TP53 gene is a well-studied tumour suppressor gene. p53 is one of the key transcription factors which regulate many cellular events, such as cell cycle, DNA damage repair, apoptosis and stress response1. Half of all human malignancies, including colon, bone, lung, breast, lymphoma, cervical, skin, gastric, ovary, brain and urological cancers, exhibit TP53 mutations, either in a single hotspot or at multiple sites, frequently accompanied by wild-type TP53 inactivation2. After p53 gene discovery, several studies have been done on how the mutational status of this gene is important in different cellular functions; the codon 72 polymorphism is one of the crucial and most studied gene alternations, which has been reported to be associated with many cancers1,2. A single nucleotide polymorphism (SNP) in exon 4 results in expression of either arginine (72R) or proline (72P) at codon 72 of TP53. This polymorphism is located in a proline-rich domain, which is essential for its DNA-binding ability to induce apoptosis. The two genetic variants (Pro 72 and Arg 72) have been thought of having different functional activities. Marin et al3 have reported that some tumour-derived TP53 mutants can bind to TP73 and inactivate its biofunction. Moreover, this binding activity of TP53 mutants can be interrupted if the TP53 variants are encoded by codon 72, a common polymorphism in the human population. Generally, Arg72 might retain a less prohibitory effect to avoiding mutant TP53 binding to TP73. The TP73 gene, a TP53 homologue, can activate TP53-responsive promoters and induce apoptosis in cells deficient of TP53. The ability of mutant TP53 to bind TP73, neutralize TP73-induced apoptosis and transform cells in cooperation with EJ-Ras was enhanced when codon 72 encoded Arg2. The Arg72 variant also appeared to interact more effectively with human papillomavirus (HPV)-E6 in vitro and degrade easily through the ubiquitin-proteasome pathway, resulting in inactivation of TP53 gene and induction of HPV-related tumour development2. Thomas et al4 have reported that Arg72 acts dominantly in transcriptional regulation of TP53 downstream targets that induce apoptosis or repress the transformation of primary cells. It has been shown that other than gain of function mutations, genetic polymorphism also plays crucial role in carcinogenesis. The Pro72 variant is crucial for specifically activating the TP53-dependent DNA repair genes in different cells, resulting in higher DNA-repair efficiency in vitro. Furthermore, Pro72 variant-expressed cells exhibit reduced micronuclei formation, compared with Arg72, suggesting that genomic instability is reduced in these cells2.

Item Type:	Article
Subjects:	Cancer Research
Depositing User:	Central Library RGCB
Date Deposited:	11 Jan 2019 06:15
Last Modified:	11 Jan 2019 06:15
URI:	http://rgcb.sciencecentral.in/id/eprint/718

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