Mikosz C A, Brickley D R, Sharkey M S, Moran T W, Conzen S D
Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois 60637, USA.
J Biol Chem. 2001 May 18;276(20):16649-54. doi: 10.1074/jbc.M010842200. Epub 2001 Feb 13.
We previously demonstrated that activation of the glucocorticoid receptor (GR) initiates an antiapoptotic signal in the immortalized human mammary epithelial cell line MCF10A that is dependent on the GR's transcriptional activity. In this study, we show that the survival role of GR activation extends to protecting human breast cancer cells undergoing apoptosis after growth factor deprivation. Serum and glucocorticoid-regulated kinase-1 (sgk), a gene previously identified as a direct transcriptional target of the activated GR in a rat mammary tumor cell line, was rapidly induced after GR activation in human mammary epithelial cells. Furthermore, in the absence of all growth factors, ectopic sgk expression inhibited apoptosis, suggesting that SGK is a survival kinase. Finally, kinase-dead SGK expression inhibited the protection from apoptosis usually seen after GR activation. These findings suggest that SGK is an important downstream target of GR-mediated survival signaling and that it is distinct from other survival kinases because it can be primarily regulated at the level of transcription.
我们先前证明，糖皮质激素受体（GR）的激活在永生化人乳腺上皮细胞系MCF10A中启动了一个抗凋亡信号，该信号依赖于GR的转录活性。在本研究中，我们表明GR激活的生存作用延伸至保护生长因子剥夺后发生凋亡的人乳腺癌细胞。血清和糖皮质激素调节激酶-1（sgk），一个先前在大鼠乳腺肿瘤细胞系中被鉴定为活化GR的直接转录靶标的基因，在人乳腺上皮细胞中GR激活后被迅速诱导。此外，在缺乏所有生长因子的情况下，异位sgk表达抑制了凋亡，表明SGK是一种生存激酶。最后，激酶失活的SGK表达抑制了通常在GR激活后所见的对凋亡的保护作用。这些发现表明SGK是GR介导的生存信号的一个重要下游靶标，并且它不同于其他生存激酶，因为它主要可以在转录水平受到调节。
