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Notch Signal Activates Hypoxia Pathway Through HES1-dependent SRC/signal Transducers and Activators of Transcription 3 Pathway

Notch Signal Activates Hypoxia Pathway Through HES1-dependent SRC/signal Transducers and Activators of Transcription 3 Pathway

Jae Ho Lee, Jinkyu Suk, Jinhwi Park, Seung Beom Kim, Sang Su Kwak, Jin Woo Kim, Chan Hee Lee, Boohyeong Byun, Jeong Keun Ahn, Cheol O Joe

Mol Cancer Res. 2009 Oct;7(10):1663-71.

PMID: 19808903

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42411934	SRC N1 human			Price

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