The regulation of the p53-mediated stress response by MDM2 and MDM4

Abstract

Exquisite control of the activity of p53 is necessary for mammalian survival. Too much p53 is lethal, whereas too little permits tumorigenesis. MDM2 and MDM4 are structurally related proteins critical for the control of p53 activity during development, homeostasis, and the response to stress. These two essential proteins regulate both the activation of p53 in response to stress and the recovery of cells following resolution of the damage, yet both are oncogenic when overexpressed. Thus, multiple regulatory circuits ensure that their activities are fine-tuned to promote tumor-free survival. Numerous diverse stressors activate p53, and much research has gone into trying to find commonalities between them that would explain the mechanism by which p53 becomes active. It is now clear that although these diverse stressors activate p53 by different biochemical pathways, one common feature is the effort they direct, through a variety of means, toward disrupting the functions of both MDM2 and MDM4. This article provides an overview of the relationship between MDM2 and MDM4, features the various biochemical mechanisms by which p53 is activated through inhibition of their functions, and proposes some emerging areas for investigation of the p53-mediated stress response.

Figure 1.

Domain structure of human homologs of MDM2 and MDM4. The amino-termini of both proteins bind p53. Only MDM2 has a nuclear localization signal (NLS). The central acidic region of MDM2, but not MDM4, binds ribosomal proteins. The RING finger domains are required for heterodimerization between MDM2 and MDM4.

Figure 2.

Multiple stressors activate p53 with several possible outcomes. Apoptosis, senescence, and growth arrest have each been shown to be tumor suppressive. However, if unrestrained, they can be lethal.

Figure 3.

Pathways for regulation of p53 by MDM2 and MDM4 under different conditions. (A) In homeostatic conditions (e.g., unstressed, adult tissues), MDM2 and MDM4 inhibit p53. (B) Following exposure to ionizing radiation, ATM phosphorylates several substrates to block the abilities of MDM2 and MDM4 to inhibit p53. (C) Ribosomal dysfunction leads to direct binding of L11 to MDM2, and to a redirection of its ubiquitin ligage activity away from p53 to MDM4. (D) Oncogenic activation causes increased expression of ARF, which binds to MDM2 and inhibits it from ubiquitylating p53.