Notch Signal Activates Hypoxia Pathway through HES1-Dependent SRC/Signal Transducers and Activators of Transcription 3 Pathway

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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-a and its target gene expression in HeLa/rtTAAfTRE-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-dependnent 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. (Mol Cancer Res 2009;7(10):1663-71)
Publisher
Amer Assoc Cancer Research
Issue Date
2009-10
Language
English
Article Type
Article
Keywords

TUMOR-SUPPRESSOR PROTEIN; GROWTH-FACTOR; INDUCIBLE FACTOR-1; VEGF EXPRESSION; TYROSINE KINASE; GENE-EXPRESSION; UP-REGULATION; STAT3; CELLS; ENHANCER

Citation

MOLECULAR CANCER RESEARCH, v.7, no.10, pp.1663 - 1671

ISSN
1541-7786
URI
http://hdl.handle.net/10203/95890
Appears in Collection
BS-Journal Papers(저널논문)
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