Regulation of transcription of hypoxia-inducible factor-1α (HIF-1α) by heat shock factors HSF2 and HSF4.
Hypoxia-inducible factor-1α (HIF-1α) is a principal regulator of angiogenesis and other cellular responses to hypoxic stress in both normal and tumor cells. To identify novel mechanisms that regulate expression of HIF-1α, we designed a genome-wide screen for expressed sequence tags (ESTs) that when transcribed in the antisense direction increase production of the HIF-1α target, vascular endothelial growth factor (VEGF), in human breast cancer cells. We discovered that heat shock factor (HSF) proteins 2 and 4-which previously have been implicated in the control of multiple genes that modulate cell growth and differentiation and protect against effects of environmental and cellular stresses-function together to maintain a steady state level of HIF-1α transcription and VEGF production in these cells. We show both HSFs bind to discontinuous heat shock element (HSE) sequences we identified in the HIF-1α promoter region and that downregulation of either HSF activates transcription of HIF-1α. We further demonstrate that HSF2 and HSF4 displace each other from HSF/HSE complexes in the HIF-1α promoter so that HIF-1α transcription is also activated by overexpression of either HSFs. These results argue that HSF2 and HSF4 regulate transcription of HIF-1α and that a critical balance between these HSF is required to maintain HIF-α expression in a repressed state. Our findings reveal a previously unsuspected role for HSFs in control of VEGF and other genes activated by canonical HIF-1α-mediated signaling.
Department of Genetics, Stanford University School of Medicine, CA, USA.
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R
Chen
J E
JE
Liliental
P E
PE
Kowalski
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Q
Lu
S N
SN
Cohen
D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D042442:Vascular Endothelial Growth Factors / Q000096:biosynthesis
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; C102948:HSF4 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D042442:Vascular Endothelial Growth Factors; C070389:HSF2 protein, human