Glucose utilization is essential for hypoxia-inducible factor 1 alpha-dependent phosphorylation of c-Jun.
Hypoxia and anoxia are important microenvironmental stresses that contribute to pathological events such as solid-tumor development. We have been investigating the effects of hypoxia and anoxia on expression of the proto-oncogene c-jun and the regulation of c-Jun/AP-1 transcription factors. In earlier work using genetically manipulated mouse embryo fibroblasts (mEFs), we found a functional relationship among c-jun expression, c-Jun N-terminal phosphorylation, and the presence of hypoxia-inducible factor 1 alpha (HIF-1 alpha), the oxygen-regulated subunit of the HIF-1 transcription factor. Both the induction of c-jun mRNA expression and c-Jun N-terminal phosphorylation in cells exposed to hypoxia or anoxia were found to be dependent on the presence of HIF-1 alpha, but this was not the case in cells exposed to less-severe hypoxia. Here we describe new findings concerning HIF-1-dependent c-Jun N-terminal phosphorylation in cells exposed to hypoxia or anoxia. Specifically, we report that hypoxia-inducible c-Jun N-terminal kinase (JNK) activity, which involves JNKs or stress-activated protein kinases (SAPKs), is dependent on enhanced glucose utilization mediated by HIF-1. These results suggest a model in which hypoxia-inducible JNK activity is connected to oxygen sensing through increased glucose absorption and/or glycolytic activity regulated by the HIF-1 system. We also found that basal threonine and tyrosine phosphorylation (within the TEY motif) of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and the corresponding ERK1/2 activity were defective in hypoxic HIF-1 alpha-null mEFs but not in wild-type mEFs, independently of glucose uptake. Therefore, the activities of both JNKs/SAPKs and ERK1/2 are sensitive to HIF-1-dependent processes in cells exposed to hypoxia or anoxia.
Laderoute
Keith R
KR
Bioscience Division, SRI International, Menlo Park, California 94025, USA. keith.laderoute@sri.com
Calaoagan
Joy M
JM
Knapp
Merrill
M
Johnson
Randall S
RS
D000818:Animals; D001483:Base Sequence; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D004247:DNA; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose