Zhang Zhuo, Zhang Ruiwen
Department of Pharmacology and Toxicology, Division of Clinical Pharmacology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Curr Cancer Drug Targets. 2005 Feb;5(1):9-20. doi: 10.2174/1568009053332618.
The feed-back auto-regulatory loop between p53 and MDM2 has been extensively investigated. MDM2 is under the transcriptional control of p53, and MDM2 acts as a negative regulator of p53. There is increasing evidence, however, supporting the notion that MDM2 has activities independent of p53. In the absence of p53, MDM2 may retain its role in cell cycle control, differentiation, cell fate determination, DNA repair, transcription regulation, signal transduction of steroid receptors, cellular response to hypoxia, internalization of surface receptors, and other processes. MDM2 also has oncogenic transformational activities independent of p53. Moreover, anti-MDM2 antisense oligonucleotides have in vitro and in vivo antitumor activity and chemosensitizing and radiosensitizing effects in several human cancer models, regardless of their p53 status. In this article, the p53 independent activities of MDM2 and its interactions with various cellular proteins are considered. The studies reviewed provide a basis for developing novel MDM2 inhibitors as a therapy against human malignancies.
p53与MDM2之间的反馈性自动调节环路已得到广泛研究。MDM2受p53的转录调控，且MDM2作为p53的负调节因子发挥作用。然而，越来越多的证据支持MDM2具有独立于p53的活性这一观点。在缺乏p53的情况下，MDM2可能在细胞周期调控、分化、细胞命运决定、DNA修复、转录调控、类固醇受体信号转导、细胞对缺氧的反应、表面受体内化及其他过程中保留其作用。MDM2还具有独立于p53的致癌转化活性。此外，抗MDM2反义寡核苷酸在体外和体内具有抗肿瘤活性，并且在多种人类癌症模型中具有化学增敏和放射增敏作用，无论其p53状态如何。在本文中，我们将探讨MDM2的p53非依赖性活性及其与各种细胞蛋白的相互作用。所综述的研究为开发新型MDM2抑制剂作为治疗人类恶性肿瘤的方法提供了依据。
