A family of latent cytoplasmic transcription factors, signal transducers and activators of transcription (STATs), mediates the responsiveness of cells to several cytokines and growth factors. Although mutations of STATs have not been described in human tumors, the activity of several members of the family, such as STAT1, STAT3 and STAT5, is deregulated in a variety of human tumors. STAT3 and STAT5 acquire oncogenic potential through constitutive phosphorylation on tyrosine, and their activity has been shown to be required to sustain a transformed phenotype. Disruption of STAT3 and STAT5 signaling in transformed cells therefore represents an excellent opportunity for targeted cancer therapy. In contrast to STAT3 and STAT5, STAT1 negatively regulates cell proliferation and angiogenesis and thereby inhibits tumor formation. Consistent with its tumor suppressive properties, STAT1 and its downstream targets have been shown to be reduced in a variety of human tumors and STAT1 deficient mice are highly susceptible to tumor formation. In recent years we have gained mechanistic understanding of the pathways whereby STATs convey signals from the cytoplasm to the nucleus. In addition, several endogenous regulators of the JAK/STAT pathway have been described - and their mechanism of action revealed - that profoundly affect signaling by STATs. Both should greatly facilitate the design of drugs with potential to modulate STAT signaling and to restore the homeostasis in tissues where STATs have gone awry.

译文

一个潜在的细胞质转录因子,信号转导子和转录激活子 (STATs) 家族,介导细胞对几种细胞因子和生长因子的反应。尽管尚未在人类肿瘤中描述STATs的突变,但在各种人类肿瘤中,该家族的几个成员 (例如STAT1,STAT3和STAT5) 的活性被解除了管制。STAT3和STAT5通过酪氨酸上的组成型磷酸化获得致癌潜力,并且已显示它们的活性是维持转化表型所必需的。因此,转化细胞中STAT3和STAT5信号的破坏代表了靶向癌症治疗的绝佳机会。与STAT3和STAT5相反,STAT1负调节细胞增殖和血管生成,从而抑制肿瘤形成。与其肿瘤抑制特性一致,STAT1及其下游靶标已显示在多种人类肿瘤中降低,并且STAT1缺陷小鼠对肿瘤形成高度敏感。近年来,我们对STATs将信号从细胞质传递到细胞核的途径获得了机械理解。此外,已经描述了JAK/STAT途径的几种内源性调节剂-并揭示了它们的作用机制-深刻影响STATs的信号传导。两者都应极大地促进药物的设计,从而有可能调节STAT信号传导并恢复STATs出现问题的组织中的稳态。

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