The MDM2-p53 pathway revisited

Abstract

The p53 tumor suppressor is a key transcription factor regulating cellular pathways such as DNA repair, cell cycle, apoptosis, angiogenesis, and senescence. It acts as an important defense mechanism against cancer onset and progression, and is negatively regulated by interaction with the oncoprotein MDM2. In human cancers, the TP53 gene is frequently mutated or deleted, or the wild-type p53 function is inhibited by high levels of MDM2, leading to downregulation of tumor suppressive p53 pathways. Thus, the inhibition of MDM2-p53 interaction presents an appealing therapeutic strategy for the treatment of cancer. However, recent studies have revealed the MDM2-p53 interaction to be more complex involving multiple levels of regulation by numerous cellular proteins and epigenetic mechanisms, making it imperative to reexamine this intricate interplay from a holistic viewpoint. This review aims to highlight the multifaceted network of molecules regulating the MDM2-p53 axis to better understand the pathway and exploit it for anticancer therapy.

Keywords: MDM2-p53 interaction; cancer therapy; oncogene; tumor suppressor.

Fig. 1. Oncogenes, tumor suppressor, and cancer.

Genomic instability caused by various factors such as viruses, cytotoxic drugs, and ionizing radiation triggers mutations in oncogenes or tumor suppressor genes and perpetuates the unstable genome on the way to malignancy. Besides mutations, other genetic alterations responsible for oncogene activation include amplification (egfr, mdm2, myc), translocation (bcr/abl), protein overexpression (MDM2, Ras) and increased protein stability (Ras). Alterations leading to tumor suppressor inactivation include loss-of-function mutations (Rb, p53), deletions (p53, DCC). Epigenetic changes such as promoter methylation can also lead to tumor suppressor inactivation (IL-2Rγ).

Fig. 2. p53, a tumor suppressor.

A: Selective Impact of p53 Modifications. Exemplary post-translational notifications via phosphorylation (P), acetylation (Ac), or ubiquitination (Ub) are depicted, which result in a specific cellular outcome in response to p53 activation and preferential activation of indicated target genes. E4F1 is an atypical ubiquitin ligase that modulates the p53 functions independently of degradation. E4F1-dependent Ub-p53 conjugates are associated with chromatin, and this induces a p53-dependent transcriptional program eliciting cell cycle arrest but not apoptosis. Following ATM activation, 14-3-3-σ is induced, and this causes dephosphorylation of p53 at S-376. HIPK2 induced S46 phosphorylation in p53 is essential for mediating its apoptotic functions. B: p53 contributes to multiple cellular processes in response to various cellular stresses via regulation of downstream targets and/or signaling pathways.

Fig. 3. MDM2 as an oncogene.

A: MDM2 structure and binding sites for various interactive proteins. MDM2 protein domains and the cellular proteins interacting with different domains are listed. Blue region: p53 binding domain (aa 19-220); Teal blue region-Nuclear localization signal (NLS); Purple region: Nuclear export signal (NES); Orange region: Acidic domain (aa 223-274); Green region: Zinc finger domain (aa 305-322); Red region: RING finger domain (aa 438-478); Yellow region: Nucleolar localization signal (NOLS). B: MDM2 contributes to multiple processes leading to and promoting the development of cancer phenotype.

Fig. 4. The traditional MDM2-p53 regulatory pathway.

The feedback regulation involving the p53 and MDM2 is shown.

Fig. 5. Several tumor suppressors and oncoproteins regulate the MDM2-p53 interaction.

Ribosomal proteins (RP-both the large subunit and small subunits) form a complex with p53 and MDM2 to inhibit MDM2-mediated p53 ubiquitination and stabilization of p53. ARF and PML sequester the MDM2 in the nucleolus, inhibiting MDM2 from binding and degrading p53. CK1 phosphorylates p53 at Thr18 in response to stress and DNA damage and, along with p53, localizes to the PML nuclear bodies. MDMX forms heteroligomers with MDM2 and induces p53 degradation. PA28γ protein interacts with both MDM2 and p53 proteins and promotes the MDM2-p53 interaction, leading to enhanced MDM2-mediated p53 ubiquitination and degradation. RYBP interacts with MDM2 to decrease MDM2-mediated p53 ubiquitination while RNF2 promotes p53 degradation. HIPK2, tumor suppressor (Ts) protein phosphorylates MDM2, promoting its proteasomal degradation while the Rb Ts forms a ternary complex with p53 and MDM2.

Fig. 6. General strategies to inhibit the MDM2-p53 interaction.

RITA= Reactivation of p53 and induction of tumor apoptosis. Ellipticine binds to mutant p53 to restore normal conformation and/or activity; PRIMA-1 reactivates mutp53 by covalent binding to the core domain.