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Isoforms of the genetp53 in the human cancer and their role in the clinical cases

Introduction. The most tumour cases happen due to the mutations in the tumor suppressor TP53 gene, because it defends and controls inner mechanisms on the cell including balance between the cell cycle arrest or cell death. p53 is a transcription factor that binds directly and specifically to the targen sequences of DNA. For example, p53 activate cell cycle arrest by expressing the genes such as the cyclin-dependent kinase inhibitor, p21., p53 activates apoptosis by expressing proapoptotic genes such as Bax and Puma. The roles of p53 in growth arrest and apoptosis are illustrated in Figure 4. P53 is also directly involved in DNA repair.[1] Growth cycle arrest: the cell cycle progression into the S phase requires the enzyme Cdk2, which can be inhibited by p21. The progression into the M phase requires Cdc2, which can be inhibited by p21, or 14-3-3s. p53 regulates the expression of these inhibitory proteins to induce growth arrest. Apoptosis: Bax is a p53-induced member of the Bcl-2 family of apoptosis promoting and preventing factors. Bax/ Bcl-2 heterodimers suppress apoptosis signaled by a number of stresses, while Bax homodimers promote apoptosis, leading to the idea that the relative level of these two proteins in a stressed cell determines life or death. It also induces P48 that activates DNA repair and prevention of damage; PTEN that inhibits IGF1 (Insulin-like growth factor1) that effects in cancer development; When situation on cell level became stable and without any risk to cancer, P53 activates negative feedback to induce MDM2 for regulation of P53[1]

Methods and materials. To study the effect of the TP53 gene on development tumor cells conducted a literature review and created scheme and illustrations.

Result. The molecular mechanisms of the decision making are still no well described. Indeed, in clinical studies, it has been difficult to link p53 mutation status to therapeutic response and clinical outcome, suggesting that additional factors may affect the p53 pathway. Despite 30 years of research on p53 demonstrating the key role of p53 in cancer treatment and prevention of cancer formation, it is still difficult in clinical studies to link p53 mutation status to cancer prognosis and cancer treatment. The weather p53δ mRNA leads to p53δ protein expression and whether p53δ has oncogenic activities. We have recently reported the analysis of p53β and p53γ mRNA expression in relation to clinical outcome and clinical markers in a cohort of 127 primary breast tumors. We determined that p53β and p53γ are not randomly expressed in breast cancer. Indeed, p53β is associated with p53γ expression, and p53γ is associated with p53 gene mutation, while p53β is associated with estrogen receptor expression (ER).Interestingly, mutant p53 breast cancer patients expressing the p53γ isoform have low cancer recurrence and an overall survival as good as wild-type p53 breast cancer patients, independent of ER status. Conversely, mutant p53 breast cancer patients devoid of p53γ expression have a particularly poor prognosis[2]. We did not observe any significant difference in wild-type p53 breast cancer patients whether they expressed p53β/ p53γ or not. Therefore, the determination of p53γ expression allows the identification of 2 populations of mutant p53 breast cancer patients with different prognoses, independent of ER status and cancer treatment. Indeed, mutant TP 53breast cancer patients expressing p53γ have a prognosis as good as wild-type p53 breast cancer patients, suggesting that they may respond better to treatment. On the other hand, mutant p53 breast cancer patients not expressing p53γ have a particularly poor prognosis probably because they poorly respond to treatment. p53γ isoform may provide an explanation of the hitherto inconsistent relationship between p53 mutation, treatment response, and outcome in breast cancer.[3,4]

Conclusion. In conclusion, the above clinical data report the expression of p53 isoforms in several types of cancer, confirming that p53 isoforms are expressed both at the mRNA and protein levels. Because p53 isoforms can regulate cell proliferation (cell cycle progression, senescence, and apoptosis) and are abnormally expressed in different cancer types, it suggests that their differential expression may disrupt the p53 response and contribute to tumor formation. Therefore, p53 isoforms may provide an explanation to the difficulties in many clinical studies to link p53 status to cancer prognosis and treatment. In cancer cells, restoration of p53β/p53γ or abolition of Δ133p53 expression would impair tumor cell growth by inducing senescence or cell death and therefore may represent novel therapeutic targets.

References:

  1. 1. Kim S, An SSA. Role of p53 isoforms and aggregations in cancer. Medicine (Baltimore) . 2016;95(26):e3993.
  2. 2. Bourdon J. P53 Isoforms Change P53 Paradigm. Mol Cell Oncol. 2014;1(4):e969136.
  3. 3. Khoury MP, Bourdon J-C. p53 Isoforms: An Intracellular Microprocessor? Genes Cancer. 2011;2(4):453–65.
  4. 4. Bourdon J. P53 Isoforms Change P53 Paradigm. Mol Cell Oncol. 2014;1(4):e969136.
  • Year: 2018
  • City: Shymkent
  • Category: Medicine

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International relations

International relations

Law

Philology

Philology is the study of language in oral and written historical sources; it is the intersection between textual criticism, literary criticism, history, and linguistics.[

Technical science

Technical science