New insights into p53 activation

Abstract

The tumor suppressor p53 is a multifunctional, highly regulated, and promoter-specific transcriptional factor that is uniquely sensitive to DNA damage and cellular stress signaling. The mechanisms by which p53 directs a damaged cell down either a cell growth arrest or an apoptotic pathway remain poorly understood. Evidence suggests that the in vivo functions of p53 seem to balance the cell-fate choice with the type and severity of damage that occurs. The concept of antirepression, or inhibition of factors that normally keep p53 at bay, may help explain the physiological mechanisms for p53 activation. These factors also provide novel chemotherapeutic targets for the reactivation of p53 in tumors harboring a wild-type copy of the gene.

Figure 1

A model for p53 activation. (A) Classical model of p53 activation. DNA damage and oxidative stress signals lead to the rapid stabilization of p53 by blocking Mdm2 through various mechanisms described in the text. Once stabilized, p53 is activated through posttranslational modifications and binds to DNA, where it can interact with other transcriptional regulators for the induction of p53-responsive target genes. (B) A refined model of p53 activation. In addition to p53 stabilization, an additional step of antirepression may occur in vivo for full p53 activation. Mdm2 and MdmX repress p53 function and activation in vivo. Removal of this repression (i.e., antirepression) may be required for subsequent steps of p53 activation such as post-translational modifications, DNA binding, and induction of p53-responsive target genes.