Alterations of the TP53 Gene in Gastric and Esophageal Carcinogenesis
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 , which induce 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.
