Wu Jin, Lu Guanting, Wang Xinjiang
Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center Buffalo, NY, USA.
Department of Pathology, Key Laboratory of Tumor Molecular Research, People's Hospital of Deyang City 173 Tai Shan North Road, Deyang 618000, Sichuan, P. R. China.
Am J Cancer Res. 2021 Dec 15;11(12):5864-5880. eCollection 2021.
The oncogenic MDM4, initially named MDMX, has been identified as a p53-interacting protein and a key upstream negative regulator of the tumor suppressor p53. Accumulating evidence indicates that MDM4 plays critical roles in the initiation and progression of multiple human cancers. MDM4 is frequently amplified and upregulated in human cancers, contributing to overgrowth and apoptosis inhibition by blocking the expression of downstream target genes of p53 pathway. Disruptors for MDM4-p53 interaction have been shown to restore the anti-tumor activity of p53 in cancer cells. MDM4 possesses multiple splicing isoforms whose expressions are driven by the presence of oncogenes in cancer cells. Some of the MDM4 splicing isoforms lack p53 binding domain and may exhibit p53-independent oncogenic functions. These features render MDM4 to be an attractive therapeutic target for cancer therapy. In the present review, we primarily focus on the detailed molecular structure of MDM4 splicing isoforms, candidate regulators for initiating MDM4 splicing, deregulation of MDM4 isoforms in cancer and potential therapy strategies by targeting splicing isoforms of MDM4.
致癌性MDM4最初被命名为MDMX，已被鉴定为一种与p53相互作用的蛋白，是肿瘤抑制因子p53的关键上游负调控因子。越来越多的证据表明，MDM4在多种人类癌症的发生和发展中起关键作用。MDM4在人类癌症中经常扩增并上调，通过阻断p53途径下游靶基因的表达促进肿瘤过度生长并抑制细胞凋亡。已证明破坏MDM4与p53的相互作用可恢复p53在癌细胞中的抗肿瘤活性。MDM4具有多种剪接异构体，其表达由癌细胞中癌基因的存在驱动。一些MDM4剪接异构体缺乏p53结合结构域，可能表现出不依赖p53的致癌功能。这些特性使MDM4成为癌症治疗中一个有吸引力的治疗靶点。在本综述中，我们主要关注MDM4剪接异构体的详细分子结构、启动MDM4剪接的候选调节因子、癌症中MDM4异构体的失调以及靶向MDM4剪接异构体的潜在治疗策略。
