Restoring p53 Function in Cancer: Novel Therapeutic Approaches for Applying the Brakes to Tumorigenesis

摘要

Abstract: p53 Tumor suppressor gene encodes for a critical cellular protein that regulate the integrity of the cell and can ninduce cell cycle arrest and/or apoptosis upon cellular stresses of several origins, including chemotherapeutics. Loss of np53 function occurs in an estimated 50% of all cancers by mutations and deletions while in the presence of wild-type p53 nalleles other mechanisms may affect the expression and activity of p53. Alternative mechanisms include methylation of nthe promoter of p53, deletion or epigenetic inactivation of the p53-positive regulator p14/ARF, elevated expression of the np53 regulators murine double minute 2 (MDM2) and MDMX, or alteration of upstream regulators of p53 such as the nkinase ATM. MDM2 is a p53 E3 ubiquitin ligase that mediates the ubiquitin-dependent degradation of p53 while np14/ARF is a small MDM2-binding protein that controls the activity of MDM2 by displacing p53 and preventing its ndegradation. MDMX antagonize p53-dependent transcriptional control by interfering with p53 transactivation function. nThe understanding of the key role of p53 inactivation in cancer development generated considerable interest in developing ncompounds that are capable of restoring the p53 functions. Several patents have been issued on such compounds. nAdenovirus-based p53 gene therapy as well as small molecules such as PRIMA that can restore the transcriptional ntransactivation function to mutant p53, or NUTLIN and RITA that interfere with MDM2-directed p53 degradation, have ntested in a preclinical setting and some of these approaches are currently in clinical development.