Notch signal activates hypoxia pathway through HES1-dependent SRC/signal transducers and activators of transcription 3 pathway.
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.
Lee
Jae Ho
JH
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
Suk
Jinkyu
J
Park
Jinhwi
J
Kim
Seung Beom
SB
Kwak
Sang Su
SS
Kim
Jin Woo
JW
Lee
Chan Hee
CH
Byun
Boohyeong
B
Ahn
Jeong Keun
JK
Joe
Cheol O
CO
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D000081247:CSK Tyrosine-Protein Kinase; D020134:Catalytic Domain / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology*; D004318:Doxycycline / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D050436:Regulatory Elements, Transcriptional / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000072056:Transcription Factor HES-1; D015533:Transcriptional Activation / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D019061:src-Family Kinases
D051792:Basic Helix-Loop-Helix Proteins; D000081247:CSK Tyrosine-Protein Kinase; D004318:Doxycycline; D018398:Homeodomain Proteins; D006877:Hydroxamic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051880:Receptors, Notch; D050796:STAT3 Transcription Factor; D000072056:Transcription Factor HES-1; D019061:src-Family Kinases; C497442:HIF1A protein, human; C494086:STAT3 protein, human; C078493:HES1 protein, human; C012589:trichostatin A; C000631346:CSK protein, human