Bowman T, Yu H, Sebti S, Dalton W, Jove R
Molecular Oncology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.
Cancer Control. 1999 Oct;6(5):427-435.
Through specific activation of gene expression, the family of proteins known as signal transducers and activators of transcription (STATs) converts extracellular stimuli into diverse biological responses. Beyond the normal signaling functions of STATs, recent evidence indicates that aberrant activation of STATs contributes to neoplastic transformation. METHODS: Current literature pertaining to the role of STAT proteins in oncogenesis is presented. Also, the rationale for developing novel approaches to disrupt STAT signaling is discussed, and the potential of STATs as anticancer targets in treating human cancer is reviewed. RESULTS: The discovery that certain oncoproteins constitutively activate specific STATs, coupled with observations that elevated STAT activity occurs frequently in a spectrum of human tumors, establishes a direct link between STAT activation and neoplastic transformation. Significantly, abrogation of STAT signaling blocks oncogenesis in model in vitro and in vivo systems. These results make STATs attractive targets for rational design of small molecule inhibitors and gene therapy approaches to disrupt STAT signaling. CONCLUSIONS: As a result of genetic, biochemical, and crystallographic analyses, the functional domains of STAT proteins have been well characterized. Based on these data, selective inhibitors of STAT function can be designed. Because disrupting STAT signaling has proven effective in blocking neoplastic transformation, it is proposed that STAT proteins represent promising targets for development of novel molecular therapeutics to treat human cancer.
通过基因表达的特异性激活，被称为信号转导子和转录激活子（STATs）的蛋白质家族将细胞外刺激转化为多种生物学反应。除了STATs的正常信号功能外，最近的证据表明STATs的异常激活有助于肿瘤转化。方法：介绍了有关STAT蛋白在肿瘤发生中作用的当前文献。此外，讨论了开发破坏STAT信号传导新方法的基本原理，并综述了STATs作为治疗人类癌症的抗癌靶点的潜力。结果：某些癌蛋白可组成性激活特定STATs这一发现，以及在一系列人类肿瘤中经常观察到STAT活性升高，在STAT激活与肿瘤转化之间建立了直接联系。重要的是，在体外和体内模型系统中，STAT信号传导的消除可阻断肿瘤发生。这些结果使STATs成为合理设计小分子抑制剂和破坏STAT信号传导的基因治疗方法的有吸引力的靶点。结论：由于遗传、生化和晶体学分析，STAT蛋白的功能结构域已得到很好的表征。基于这些数据，可以设计STAT功能的选择性抑制剂。由于已证明破坏STAT信号传导在阻断肿瘤转化方面有效，因此提出STAT蛋白是开发治疗人类癌症的新型分子疗法的有希望的靶点。
