Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
Mol Cancer Res. 2009 Oct;7(10):1663-71. doi: 10.1158/1541-7786.MCR-09-0191. Epub 2009 Oct 6.
We report a Notch signal-induced pathway that leads to transcriptional activation of HIF1-alpha gene. HeLa/rtTAA/TRE-N1-IC cell line capable of doxycycline-induced expression of human Notch1-IC was established. The induction of Notch signaling activates HIF1-alpha and its target gene expression in HeLa/rtTAA/TRE-N1-IC cells. Notch signaling enhanced signal transducers and activators of transcription 3 (STAT3) phosphorylation required for HIF1-alpha expression. SRC kinase was found to be responsible for the enhanced STAT3 phosphorylation in response to Notch signaling. Activation of SRC/STAT3 pathway by Notch signaling was dependent on the expression of Notch effector HES1 transcription factor. The induction of HES1 enhanced STAT3 phosphorylation at Tyr 705 as well as SRC phosphorylation at Tyr 416 in inducible HeLa/rtTAA/TRE-HES1 cells, which express HES1 in response to doxycycline treatment. However, the treatment of Trichostatin A that interferes with HES1 transcriptional regulation did not affect STAT3 phosphorylation, and the expression of dominant negative HES1 failed to interfere with HES1-dependent SRC/STAT3 pathway. These observations have led us to the conclusion that HES1-dependent activation of SRC/STAT3 pathway is independent of HES1 transcription regulation. This study first reports HES1-dependent SRC/STAT3 pathway that provides a functional link between Notch signaling and hypoxia pathway.
我们报告了一个 Notch 信号诱导途径，该途径导致 HIF1-α 基因的转录激活。建立了能够诱导表达人 Notch1-IC 的 HeLa/rtTAA/TRE-N1-IC 细胞系。Notch 信号的诱导激活了 HeLa/rtTAA/TRE-N1-IC 细胞中的 HIF1-α及其靶基因的表达。Notch 信号增强了信号转导子和转录激活子 3（STAT3）磷酸化，这是 HIF1-α表达所必需的。发现 SRC 激酶负责响应 Notch 信号增强 STAT3 磷酸化。Notch 信号对 SRC/STAT3 途径的激活依赖于 Notch 效应因子 HES1 转录因子的表达。HES1 的诱导增强了可诱导的 HeLa/rtTAA/TRE-HES1 细胞中 STAT3 在 Tyr705 处和 SRC 在 Tyr416 处的磷酸化，这些细胞在受到强力霉素处理时表达 HES1。然而，干扰 HES1 转录调节的 Trichostatin A 的处理并不影响 STAT3 磷酸化，并且显性负性 HES1 的表达未能干扰 HES1 依赖性 SRC/STAT3 途径。这些观察结果使我们得出结论，HES1 依赖性 SRC/STAT3 途径的激活独立于 HES1 转录调节。本研究首次报道了 HES1 依赖性 SRC/STAT3 途径，该途径提供了 Notch 信号与缺氧途径之间的功能联系。
