role of tumor protein 53 mutations in common human cancers and targeting the murine double minute 2-P53 interaction for cancer therapy

ABSTRACT

The gene TP53 [also known as protein 53 or tumor protein 53], encoding transcription factor P53, is mutated or deleted in half of human cancers, demonstrating the crucial role of P53 in tumor suppression. There are reports of nearly 250 independent germ line TP53 mutations in over 100 publications. The P53 protein has the structure of a transcription factor and, is made up of several domains. The main function of P53 is to organize cell defense against cancerous transformation. P53 is a potent transcription factor that is activated in response to diverse stresses, leading to the induction of cell cycle arrest, apoptosis or senescence. The P53 tumor suppressor is negatively regulated in cells by the murine double minute 2 [MDM2] protein. Murine double minute 2 favors its nuclear export, and stimulates its degradation. Inhibitors of the P53- MDM2 interaction might be attractive new anticancer agents that could be used to activate wild-type P53 in tumors. Down regulation of MDM2 using an small interfering RNA [siRNA] approach has recently provided evidence for a new role of MDM2 in the P53 response, by modulating the inhibition of the cyclin-dependent kinase 2 [cdk2] by P21/WAF1 [also known as cyclin-dependent kinase inhibitor 1 or CDKinteracting protein 1]