Induction of apoptosis and Fas receptor/Fas ligand expression by ischemia/reperfusion in cardiac myocytes requires serine 727 of the STAT-1 transcription factor but not tyrosine 701
Induction of apoptosis and Fas receptor/Fas ligand expression by ischemia/reperfusion in cardiac myocytes requires serine 727 of the STAT-1 transcription factor but not tyrosine 701
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DOI：
10.1074/jbc.m101177200
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发表时间：
2001-07-27
影响因子：
4.8
通讯作者：
Latchman, DS
中科院分区：
文献类型：
--
作者：
Stephanou, A;Scarabelli, TM;Latchman, DS
之前我们报道过缺血会导致细胞凋亡，并伴有 Tyr-701 磷酸化以及信号转导子和转录激活子 1 (STAT-1) 的表达和转录活性增加。在本研究中，我们发现心肌细胞暴露于缺血会诱导另一个位点 Ser-727 处的 STAT-1 磷酸化。此外，STAT-1 对于缺血/再灌注 (I/R) 诱导 Fas 受体和 Fas 配体表达至关重要。 Fas 和 FasL 的转录激活依赖于 STAT-1 的 Ser-727，但不依赖于 Tyr-701。同样，I/R 期间 STAT-1 增强心肌细胞死亡需要 Ser-727，而不是 Tyr-701。此外，抑制 p38 通路可阻止暴露于 I/R 的心肌细胞中 Fas 和 FasL 的诱导和转录激活，而抑制 p42/p44 MAPK 则没有效果。最后，I/R 还诱导离体完整心脏的心室肌细胞中 Ser-727 上的 STAT-1 磷酸化和 Fas/FasL 表达。这些结果表明，在暴露于 I/R 的心肌细胞中，Fas/FasL 基因和细胞凋亡被 STAT-1 激活，并且这些效应依赖于 STAT-1 的 Ser-727 而不是 Tyr-701 磷酸化位点。
Previously we reported that ischemia results in apoptosis and is accompanied by phosphorylation on Tyr-701 and increased expression and transcriptional activity of the signal transducer and activator of transcription-1 (STAT-1). In the present study, we show that exposure of cardiomyocytes to ischemia induced the phosphorylation of STAT-1 at another site, Ser-727. Moreover, STAT-1 is critical for the induction of Fas receptor and Fas ligand expression by ischemia/reperfusion (I/R). Transcriptional activation of Fas and FasL was dependent on Ser-727 of STAT-1 but was independent of Tyr-701. Similarly, Ser-727 but not Tyr-701 was required for enhancement of cardiomyocyte cell death by STAT-1 during I/R. In addition, inhibition of the p38 pathway prevented the induction and transcriptional activation of Fas and FasL in cardiac cells exposed to I/R, whereas inhibition of p42/p44 MAPK had no effect. Finally, I/R also induced phosphorylation of STAT-1 on Ser-727 and expression of Fas/FasL in ventricular myocytes in the intact heart ex vivo. These results indicate that Fas/FasL genes and apoptosis are activated by STAT-1 in cardiac myocytes exposed to I/R and these effects are dependent on the Ser-727 but not the Tyr-701 phosphorylation sites of STAT-1.