Bromberg J, Darnell J E
Laboratory of Molecular Cell Biology, Rockefeller University, New York, NY 10021, USA.
Oncogene. 2000 May 15;19(21):2468-73. doi: 10.1038/sj.onc.1203476.
The STAT proteins (Signal Transducers and Activators of Transcription), were identified in the last decade as transcription factors which were critical in mediating virtually all cytokine driven signaling. These proteins are latent in the cytoplasm and become activated through tyrosine phosphorylation which typically occurs through cytokine receptor associated kinases (JAKs) or growth factor receptor tyrosine kinases. Recently a number of non-receptor tyrosine kinases (for example src and abl) have been found to cause STAT phosphorylation. Phosphorylated STATs form homo- or hetero-dimers, enter the nucleus and working coordinately with other transcriptional co-activators or transcription factors lead to increased transcriptional initiation. In normal cells and in animals, ligand dependent activation of the STATs is a transient process, lasting for several minutes to several hours. In contrast, in many cancerous cell lines and tumors, where growth factor dysregulation is frequently at the heart of cellular transformation, the STAT proteins (in particular Stats 1, 3 and 5) are persistently tyrosine phosphorylated or activated. The importance of STAT activation to growth control in experiments using anti-sense molecules or dominant negative STAT protein encoding constructs performed in cell lines or studies in animals lacking specific STATs strongly indicate that STATs play an important role in controlling cell cycle progression and apoptosis. Stat1 plays an important role in growth arrest, in promoting apoptosis and is implicated as a tumor suppressor; while Stats 3 and 5 are involved in promoting cell cycle progression and cellular transformation and preventing apoptosis. Many questions remain including: (1) a better understanding of how the STAT proteins through association with other factors increase transcription initiation; (2) a more complete definition of the sets of genes which are activated by different STATs and (3) how these sets of activated genes differ as a function of cell type. Finally, in the context of many cancers, where STATs are frequently persistently activated, an understanding of the mechanisms leading to their constitutive activation and defining the potential importance of persistent STAT activation in human tumorigenesis remains. Oncogene (2000).
信号转导子与转录激活子（STAT）蛋白在过去十年中被鉴定为转录因子，在介导几乎所有细胞因子驱动的信号传导中起关键作用。这些蛋白在细胞质中呈潜伏状态，通过酪氨酸磷酸化而被激活，酪氨酸磷酸化通常通过细胞因子受体相关激酶（JAK）或生长因子受体酪氨酸激酶发生。最近发现许多非受体酪氨酸激酶（例如src和abl）可导致STAT磷酸化。磷酸化的STAT形成同二聚体或异二聚体，进入细胞核，并与其他转录共激活因子或转录因子协同作用，导致转录起始增加。在正常细胞和动物中，STAT的配体依赖性激活是一个短暂的过程，持续几分钟到几小时。相比之下，在许多癌细胞系和肿瘤中，生长因子失调常常是细胞转化的核心，STAT蛋白（特别是Stat1、3和5）持续酪氨酸磷酸化或被激活。在使用反义分子或在缺乏特定STAT的动物中进行的细胞系实验或研究中，使用显性负性STAT蛋白编码构建体进行的实验表明，STAT激活对生长控制的重要性强烈表明STAT在控制细胞周期进程和细胞凋亡中起重要作用。Stat1在生长停滞、促进细胞凋亡中起重要作用，并被认为是一种肿瘤抑制因子；而Stat3和5则参与促进细胞周期进程和细胞转化，并防止细胞凋亡。许多问题仍然存在，包括：（1）更好地理解STAT蛋白如何通过与其他因子结合来增加转录起始；（2）更完整地定义由不同STAT激活的基因集；（3）这些激活的基因集如何因细胞类型而异。最后，在许多癌症中，STAT经常持续激活，了解导致其组成性激活的机制以及确定持续STAT激活在人类肿瘤发生中的潜在重要性仍然存在。《癌基因》（2000年）
