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(Circulation Research. 2007;100:13.)
© 2007 American Heart Association, Inc.

Editorials

A Novel Application for Murine Double Minute 2 Antagonists

The p53 Tumor Suppressor Network Also Controls Angiogenesis

Bernd R. Binder

From the Department of Vascular Biology and Thrombosis Research, Center for Biomolecular Medicine and Pharmacology, Medical University Vienna.

Correspondence to Bernd R. Binder, Department of Vascular Biology and Thrombosis Research, Center for Biomolecular Medicine and Pharmacology, Medical University Vienna, Schwarzspanierstr. 17, 1090, Austria. E-mail bernd.binder@meduniwien.ac.at

Key Words: angiogenesis • MDM2 • p53 • nutlin-3

An extract of the first 250 words of the full text is provided, because this article has no 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 gene^2–4 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 MDM2^6,7 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 Thus, mutations in the p53 gene or an increase in MDM2 protein impair the effectiveness of p53-dependent proapoptotic and cell-cycle arrest mechanisms and thereby favor the development of tumors. In addition, MDM2 has also p53-independent activities^10,11 through interactions with proteins involved in controlling cell proliferation and survival. This concatenation of data indicated that disruption of the p53–MDM2 autoregulatory feedback loop as well as inhibition of MDM2 would be a suitable strategy for tumor therapy. In fact, Vassilev et al¹² recently developed a class of small molecules, the nutlins (eg, nutlin-3, . . . [Full Text of this Article]

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