MDM2, MDMX and p53 in oncogenesis and cancer therapy

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Abstract

The MDM2 and MDMX (also known as HDMX and MDM4) proteins are deregulated in many human cancers and exert their oncogenic activity predominantly by inhibiting the p53 tumour suppressor. However, the MDM proteins modulate and respond to many other signalling networks in which they are embedded. Recent mechanistic studies and animal models have demonstrated how functional interactions in these networks are crucial for maintaining normal tissue homeostasis, and for determining responses to oncogenic and therapeutic challenges. This Review highlights the progress made and pitfalls encountered as the field continues to search for MDM-targeted antitumour agents.

Key Points

  • MDM2 and MDMX are RING domain proteins that exert their oncogenic effects primarily by inhibiting the p53 tumour suppressor protein.

  • Each protein is overexpressed in diverse tumour types by mechanisms including gene amplification and post-translational stabilization; this is generally more frequent in tumours with a wild-type TP53 allele.

  • Despite their similar structures, only MDM2 has intrinsic E3 ubiquitin ligase activity. Although MDM2 alone can inhibit p53, its RING-dependent heterodimerization with MDMX has an important role in p53 inhibition.

  • Both MDM2 and MDMX interact with multiple other partners. Aberrant interactions with these partners may also affect gene expression and genome stability.

  • Structure-based drug design has yielded several MDM antagonists that block MDM–p53 interactions, leading to p53 activation. At least one agent has progressed to clinical trials.

  • Systems biology studies are providing the rationale for using MDM protein antagonists in combination with both approved and experimental pathway-targeted anticancer drugs.

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Figure 1: Transcriptional and post-translational regulation of MDM2 and MDMX.

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Acknowledgements

Studies relevant to the topics discussed here were supported by grants from the US National Institutes of Health (R01-CA61449 and R03-MH089489-01), Cancer Center Support Grant CA014195 and a sanofi-aventis sponsored research grant awarded to G.M.W.

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Correspondence to Geoffrey M. Wahl.

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DATABASES

ClinicalTrials.gov

National Cancer Institute Drug Dictionary

NCI Drug Dictionary

17-AAG

AZD6244

cisplatin

RG7112

topotecan

vemurafenib

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Glossary

Antagonists

Chemical substances that interfere with or inhibit the physiological activity of other biological entities such as proteins or enzymes.

miRNAs

Derived from an RNA polymerase II transcribed precursor, miRNAs are a class of non-protein coding mRNA that reduces the expression of cellular proteins through various mechanisms.

Hemizygous

A genetic status in which one allelic copy of a gene is deleted or otherwise inactivated.

Haploinsufficiency

A genetic status in which a single wild-type copy of an allelic pair is present, but the level of expression of the product is insufficient to give wild-type function.

Myeloablation

The depletion of bone marrow cells.

Neoadjuvant therapy

Administration of therapeutic agents to reduce tumour volume before giving a primary treatment such as surgery.

IC50

The half-maximal inhibitory concentration, which is the concentration of a compound causing 50% inhibition of biological or biochemical function.

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