Bond Gareth L, Hu Wenwei, Levine Arnold J
School of Natural Sciences, Institute for Advanced Study, Princeton, NJ 08540, USA.
Curr Cancer Drug Targets. 2005 Feb;5(1):3-8. doi: 10.2174/1568009053332627.
Twelve years ago, the Mdm2 oncogene was shown to bind to and inhibit the tumor suppressor protein, p53. During the past 12 years, both genetic and biochemical studies have demonstrated that Mdm2 is a key negative regulator of the tumor suppressor p53. Mdm2 and p53 form an oscillating auto-regulatory feedback loop, which is tightly controlled to allow the appropriate response to environmental stresses in order to suppress tumor formation. When Mdm2 activity is inappropriately heightened, as it is in many human tumors, p53 activity is attenuated and tumor susceptibility arises. The p53 gene is mutated in 50% of all human tumors, but in those tumors that retain wild type p53, inhibiting Mdm2 activity could activate p53 tumor suppression and therefore provide a therapeutic strategy for the treatment of cancer.
12年前，人们发现Mdm2癌基因能与肿瘤抑制蛋白p53结合并抑制它。在过去的12年里，遗传学和生物化学研究均表明，Mdm2是肿瘤抑制因子p53的关键负调控因子。Mdm2和p53形成一个振荡的自动调节反馈环，该反馈环受到严格控制，以便对环境应激做出适当反应，从而抑制肿瘤形成。当Mdm2活性像在许多人类肿瘤中那样不适当地升高时，p53活性就会减弱，肿瘤易感性就会出现。在所有人类肿瘤中，50%的肿瘤p53基因发生了突变，但在那些保留野生型p53的肿瘤中，抑制Mdm2活性可以激活p53的肿瘤抑制作用，因此可为癌症治疗提供一种治疗策略。
