A Novel Application for Murine Double Minute 2 Antagonists

Abstract

Impairment of the p53 tumor suppressor network1 is thought to be involved in a large percentage of tumors either by mutations in the p53 gene2–4 or by increased expression of its major control system, the MDM25 (murine double minute 2; HDM2 for its human equivalent). It is important to realize that levels of p53 are subjected to an autoregulatory feedback loop by MDM26,7 as p53 upregulates MDM2 gene expression and MDM2 protein in turn binds to p53. MDM2 is an E3 ubiquitin ligase and transports p53 to the cytoplasm where it promotes p53 ubiquitination and degradation by the proteasome. In human cancer, increased levels of MDM26 are caused either by gene amplification, increased expression induced by activated p53, stabilization by an aberrantly spliced form of HMDX8, or augmented translation. In addition to these mechanisms, functional single-nucleotide polymorphisms (SNP) such as the 1 at nucleotide 309 (SNP309) in the MDM2 gene can modulate MDM2 expression and cause increased tumor progression.9 …