title: The response of c-jun/AP-1 to chronic hypoxia is hypoxia-inducible factor 1 alpha dependent.
abstract: Hypoxia (low-oxygen tension) is an important physiological stress that influences responses to a wide range of pathologies, including stroke, infarction, and tumorigenesis. Prolonged or chronic hypoxia stimulates expression of the stress-inducible transcription factor gene c-jun and transient activation of protein kinase and phosphatase activities that regulate c-Jun/AP-1 activity. Here we describe evidence obtained by using wild-type and HIF-1 alpha nullizygous mouse embryonic fibroblasts (mEFs) that the induction of c-jun mRNA expression and c-Jun phosphorylation by prolonged hypoxia are completely dependent on the presence of the oxygen-regulated transcription factor hypoxia-inducible factor 1 alpha (HIF-1 alpha). In contrast, transient hypoxia induced c-jun expression in both types of mEFs, showing that the early or rapid induction of this gene is independent of HIF-1 alpha. These findings indicate that the c-jun gene has a biphasic response to hypoxia consisting of inductions that depend on the degree or duration of exposure. To more completely define the relationship between prolonged hypoxia and c-Jun phosphorylation, we used mEFs from mice containing inactivating mutations of critical phosphorylation sites in the c-Jun N-terminal region (serines 63 and 73 or threonines 91 and 93). Exposure of these mEFs to prolonged hypoxia demonstrated an absolute requirement for N-terminal sites for HIF-1 alpha-dependent phosphorylation of c-Jun. Taken together, these findings suggest that c-Jun/AP-1 and HIF-1 cooperate to regulate gene expression in pathophysiological microenvironments.
authors.affiliation: Pharmaceutical Discovery Division, SRI International, Menlo Park, California 94025, USA. keith.laderoute@sri.com
authors.forename: Keith R
authors.initials: KR
authors.lastname: Laderoute
authors.forename: Joy M
authors.initials: JM
authors.lastname: Calaoagan
authors.forename: Cindy
authors.initials: C
authors.lastname: Gustafson-Brown
authors.forename: A Merrill
authors.initials: AM
authors.lastname: Knapp
authors.forename: Guo-Chun
authors.initials: GC
authors.lastname: Li
authors.forename: Holly L
authors.initials: HL
authors.lastname: Mendonca
authors.forename: Heather E
authors.initials: HE
authors.lastname: Ryan
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Wang
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics* / Q000502:physiology*; D002460:Cell Line; D005786:Gene Expression Regulation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014157:Transcription Factors