title: Hypoxia induces AP-1-regulated genes and AP-1 transcription factor binding in human endothelial and other cell types.
abstract: Hypoxia results in differential expression of specific genes in certain cell types. In endothelial cells, hypoxia activates several genes that are known to be inducible by transcription factor AP-1, including endothelin-1 and platelet-derived growth factor-B (PDGF-B). In this study we demonstrated that other AP-1-inducible genes are activated by hypoxia in these cells, including collagenase IV and c-jun, and sought to correlate the activation of genes by hypoxia with the activation of transcription factor AP-1. Depending upon the type of cell studied, hypoxic exposure resulted in the induction of AP-1 transcription factor DNA-binding activity with wide variations in levels of binding. The magnitude of activation of transcription factor AP-1 by hypoxia did not always strictly correlate with the level of induction of AP-1-inducible genes. This finding indicates a requirement for additional mechanisms of controlling transcription beyond the simple activation of AP-1 factor DNA-binding activity for the activation of AP-1-inducible genes during hypoxia. Hypoxia has been reported to lower the intracellular redox potential. The effect of redox state changes on AP-1 transcription factor activity and on the activation of AP-1-inducible genes was also studied. PDTC, a potent reducing agent, activated the AP-1 transcription factor in HeLa cells, and also resulted in increased accumulation of c-jun mRNA in these cells. In contrast to PDTC-mediated activation of the AP-1 transcription factor and the subsequent induction of the AP-1-regulated c-jun gene, hypoxic activation of AP-1 transcription factor binding to its cognate DNA sequence did not activate the c-jun gene in HeLa cells, thus documenting distinct differences in signals generated by the reducing intracellular microenvironments created by hypoxia and PDTC. These results demonstrate the induction of AP-1 transcription factor activity by hypoxic environments, but suggest that additional factors or cell-specific signals are involved in the regulation of hypoxia-induced genes.
authors.affiliation: Cancer Research Center, Boston University Medical Center, MA 02118, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Bandyopadhyay
authors.forename: M
authors.initials: M
authors.lastname: Phelan
authors.forename: D V
authors.initials: DV
authors.lastname: Faller
mesh_terms: D001665:Binding Sites; D015687:Cell Hypoxia; D002478:Cells, Cultured; D017364:Collagenases / Q000235:genetics; D016232:Endothelins / Q000235:genetics; D004727:Endothelium / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D016758:Genes, jun; D006367:HeLa Cells; D006801:Humans; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D016232:Endothelins; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D017364:Collagenases