Shaikh Mohammad F, Morano William F, Lee John, Gleeson Elizabeth, Babcock Blake D, Michl Josef, Sarafraz-Yazdi Ehsan, Pincus Matthew R, Bowne Wilbur B
Drexel University College of Medicine, Department of Surgery, Philadelphia, PA, USA.
Department of Pathology, SUNY Downstate Medical Center, Brooklyn, NY, USA.
Ann Clin Lab Sci. 2016 Dec;46(6):627-634.
The mouse/murine protein, MDM2, and its human homolog, HDM2, are important negative regulators of the p53 tumor suppressor protein. In normal, untransformed cells, MDM2 levels are tightly regulated to control expression of p53 and apoptosis. Conversely, MDM2 expression appears inherently higher in multiple types of cancer cells, thereby supporting its role as a suppressor of p53 pro-apoptotic activity. MDM2 amplification ranges between two- and ten-fold as reported in brain, breast, lung, and soft tissue tumors. MDM2 regulates p53 by two mechanisms: acting as a physical blockade of the transcriptional activation domain and E3 ubiquitin ligase. In addition to its relationship with p53, MDM2 behaves as an independent oncogene. These inherent characteristics make MDM2 a promising target for developing anti-cancer therapies. Investigators are now exploring both p53- dependent and independent cancer cell death pathways by targeting MDM2. Disrupting MDM2-p53 interaction with resultant increase in p53 induces cancer cell cycle arrest and apoptosis. Targeting over-expressed MDM2 on cancer cell membranes disrupts membrane integrity by pore formation, causing membrane destabilization and rapid cancer cell-specific necrosis. In this review, evidence supporting the evolving role of MDM2 as an anti-cancer target and a molecular-based tumor biomarker will be discussed.
小鼠/鼠源蛋白MDM2及其人类同源物HDM2是p53肿瘤抑制蛋白的重要负调控因子。在正常的未转化细胞中，MDM2水平受到严格调控，以控制p53的表达和细胞凋亡。相反，MDM2在多种癌细胞中的表达似乎天生就较高，从而支持其作为p53促凋亡活性抑制剂的作用。如在脑、乳腺、肺和软组织肿瘤中报道的那样，MDM2扩增范围在2至10倍之间。MDM2通过两种机制调节p53：作为转录激活域的物理阻断剂和E3泛素连接酶。除了其与p53的关系外，MDM2还表现为一种独立的癌基因。这些内在特性使MDM2成为开发抗癌疗法的一个有前景的靶点。研究人员现在正在通过靶向MDM2探索p53依赖性和非依赖性癌细胞死亡途径。破坏MDM2与p53的相互作用，导致p53增加，从而诱导癌细胞周期停滞和凋亡。靶向癌细胞膜上过度表达的MDM2通过形成孔道破坏膜的完整性，导致膜不稳定和癌细胞特异性快速坏死。在这篇综述中，将讨论支持MDM2作为抗癌靶点和基于分子的肿瘤生物标志物不断演变的作用的证据。
