Alterations of the TP53 gene in gastric and esophageal carcinogenesis

Abstract

TP53 genes is one of more important tumor suppressor gene, which acts as a potent transcription factor with fundamental role in the maintenance of genetic stability. The development of esophageal and gastric cancers is a multistep process resulting in successive accumulation of genetic alterations that culminates in the malignant transformation. Thus, this study highlights the participation of the main genetic alterations of the TP53 gene in esophageal and gastric carcinogenesis. Among these changes, high frequency of TP53 mutations, loss of heterozygosity (LOH), overexpression of the p53 protein, and consequently loss of p53 function, which would be early events in esophageal and gastric cancers, as well as an important biomarker of the prognosis and treatment response. Furthermore, Single Nucleotide Polymorphisms (SNPs) of TP53 have been implicated in the development and prognosis of several cancers, mainly TP53 codon 72 polymorphism whose role has been extensively studied in relation to susceptibility for esophageal and gastric cancer development.

Figure 1

The p53 signaling pathway: In normal conditions (black arrows), p53 is maintained at very low levels. p53 is downregulated by MDM2 (murine double minute 2) and MDMX (Mdm4 p53 binding protein homolog mouse). MDM2 is an E3 ubiquitin ligase, which controls p53 proteasomal degradation. MDMX lacks the E3 ligase function and suppresses the transcriptional activity of p53, which is independent of MDM2. It also forms a heterodimeric complex with MDM2 and stimulates MDM2-mediated p53 degradation. The expression of MDM2 is controlled by p53 itself through a negative feedback loop. In stress conditions (red arrows) p53 responds to a range of environmental and intracellular stresses, including agents that cause DNA damage, ultraviolet radiation, and oxidative stress.In damage response are activated several kinases (ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR)), which cause conformational changes in p53, MDMX, and MDM2 blocking their interactions and resulting in p53 stabilization. Activated p53 protein subsequently transactivates expression of several target genes, such as the cyclin-dependent kinase inhibitor protein p21^WAF1, which induce G₁/S arrest, proapoptotic genes particularly those involved in the mitochondrial pathway of apoptosis, such as BAX, and genes involved in DNA repair, such as GADD45/PCNA.