Mdm2 and MdmX as Regulators of Gene Expression

Abstract

p53 is an important tumor suppressor, functioning as a transcriptional activator and repressor. Upon receiving signals from multiple stress related pathways, p53 regulates numerous activities such as cell cycle arrest, senescence, and cell death. When p53 activities are not required, the protein is held in check by interacting with 2 key homologous regulators, Mdm2 and MdmX, and a search for inhibitors of these interactions is well underway. However, it is now recognized that Mdm2 and MdmX function beyond simple inhibition of p53, and a complete understanding of Mdm2 and MdmX functions is ever more important. Indeed, increasing evidence suggests that Mdm2 and MdmX affect p53 target gene specificity and influence the activity of other transcription factors, and Mdm2 itself may even function as a transcription co-factor through post-translational modification of chromatin. Additionally, Mdm2 affects post-transcriptional activities such as mRNA stability and translation of a variety of transcripts. Thus, Mdm2 and MdmX influence the expression of many genes through a wide variety of mechanisms, which are discussed in this review.

Keywords: Hdm2; Mdm4; transcription; translation.

Figure 1.

Mdm2 and MdmX regulate gene expression by multiple modes. Mdm2 and MdmX affect p53-mediated target gene selectivity both directly and indirectly. First, they regulate enzymes that catalyze p53 post-translational modifications as well as p53-mediated chromatin remodeling and p53 interacting co-factors that influence target gene selectivity. Through direct binding to p53, they also regulate its activities. Second, Mdm2 and MdmX influence the activity of transcription factors other than p53. Third, Mdm2 also interacts with chromatin. where it influences chromatin modifications. Fourth, Mdm2 regulates the stability and translation of a number of mRNA transcripts.