Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Rd N., Mississauga, Canada; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Canada.
Institute of Animal Breeding and Genetics, University of Veterinary Medicine, A-1210 Vienna, Austria.
Biochim Biophys Acta Gen Subj. 2022 Mar;1866(3):130058. doi: 10.1016/j.bbagen.2021.130058. Epub 2021 Nov 11.
The STAT family of transcription factors control gene expression in response to signals from various stimulus. They display functions in diseases ranging from autoimmunity and chronic inflammatory disease to cancer and infectious disease.
This work uses an approach informed by structural data to explore how domain-specific structural variations, post-translational modifications, and the cancer genome mutational landscape dictate STAT member-specific activities.
We illustrated the structure-function relationship of STAT proteins and highlighted their effect on member-specific activity. We correlated disease-linked STAT mutations to the structure and cancer genome mutational landscape and proposed rational drug targeting approaches of oncogenic STAT pathway addiction.
Hyper-activated STATs and their variants are associated with multiple diseases and are considered high value oncology targets. A full understanding of the molecular basis of member-specific STAT-mediated signaling and the strategies to selectively target them requires examination of the difference in their structures and sequences.
STAT 转录因子家族控制基因表达，以响应来自各种刺激的信号。它们在从自身免疫和慢性炎症性疾病到癌症和传染病等疾病中发挥作用。
这项工作使用了一种基于结构数据的方法来探索特定于结构域的结构变化、翻译后修饰以及癌症基因组突变景观如何决定 STAT 成员特异性活性。
我们说明了 STAT 蛋白的结构-功能关系，并强调了它们对成员特异性活性的影响。我们将与疾病相关的 STAT 突变与结构和癌症基因组突变景观相关联，并提出了针对致癌 STAT 通路成瘾的合理药物靶向方法。
高活性 STAT 及其变体与多种疾病相关，被认为是具有高价值的肿瘤学靶标。要充分了解成员特异性 STAT 介导的信号转导的分子基础以及选择性靶向它们的策略，需要检查它们结构和序列上的差异。
