鼠双微染色体2作为肿瘤治疗新靶点的研究进展

Progress of murine double minute 2 as a new target for tumor therapy

鼠双微染色体2(mdm2)是一种进化保守的癌基因,其编码蛋白参与细胞调控的多条通路,在肿瘤的发生和发展过程中发挥重要作用。很多人类肿瘤中都存在着mdm2基因扩增和(或)MDM2蛋白的过度表达。MDM2主要通过与P53蛋白中Phe19,Trp23和Leu26位点的结合参与MDM2-P53作用的负反馈环。P53蛋白可以促进MDM2的表达,而MDM2则可以通过与P53蛋白的结合介导其出核,减弱其转录活性,并促进其降解,发挥P53依赖性的MDM2活性作用。同时,MDM2还可以通过与P21蛋白、早幼粒细胞白血病蛋白、成视网膜细胞瘤蛋白Rb等的结合而不依赖于P53促进肿瘤的生长。低氧环境及肿瘤抑制因子PTEN、抑癌蛋白ARF等刺激因子均可以通过对MDM2的活性调控影响MDM2的功能发挥。在此基础上,针对MDM2-P53之间相互作用的化合物研究受到了较大关注。其中MDM2特异性拮抗剂nutlins高度模拟了P53肽段进而与P53竞争结合MDM2表面的P53口袋域,干扰MDM2-P53的相互作用,从而导致了P53的稳定以及P53通路的激活。关于nutlins在肿瘤细胞周期、凋亡、新生血管形成及药物合用等方面的研究结果表明,其作为分子工具可有效地抑制或阻断MDM2作用,为肿瘤的治疗提供了全新的思路和策略。

Murine double minute 2 （mdm2）, as an oncogene, eontribates to several pathways involved in cellular regulation, which plays an important role in cancer etiology and progression. Overexpression of MDM2, found in many human tumors, effectively im- pairs P53 function. MDM2 binds the P53 tumor suppressor protein by Phe19, Trp23, and Leu26 with high affinity and negatively modulates its transcriptional ac- tivity and stability. P53 can activate MDM2 expression which, in turn, leads to the repression of P53 by three mechanisms. First, MDM2 binds P53 at its transacti- ration domain and blocks its ability to activate tran- scription. Second, it is involved in the nuclear export of P53. Third, MDM2 serves as a ubiquitin ligase that promotes P53 degradation. Besides, MDM2 may also interact with other proteins like P21, promyelocytie leukemia protein and Rb to exert P53-independent ac- tivities. Several main regulators, such as hypoxia, PTEN and ARF, were also presented in this review. Furthermore, nutlins, the specific antagonists of MDM2, can stabilize P53 by inhibition of MDM2-P53 interaction and offer a novel strategy for cancer thera- py, indicating the potential value of MDM2 for new therapeutics against cancer.