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Hypoxia induces c-fos transcription via a mitogen-activated protein kinase-dependent pathway.

Abstract
Hypoxia is a pathophysiological condition that occurs during injury, ischemia, and stroke. It is characterized by a decrease of reactive oxygen intermediates and a change of the intracellular redox level. In tumors hypoxia is regarded as a trigger for enhanced growth and metastasis. Here we report that in HeLa cells, hypoxic conditions induce the transcriptional activation of c-fos transcription via the serum response element. Mutations in the binding site for the ternary complex factor Elk-1 and the serum response factor abolished this induction, indicating that a ternary complex at the serum response element is necessary for the induction of the c-fos gene under hypoxia. The transcription factor Elk-1 was covalently modified by phosphorylation in response to hypoxia. Furthermore this hyperphosphorylation of Elk-1, the activation of mitogen-activated protein kinase (MAPK), and the induction of c-fos transcripts were blocked by PD98059, a specific inhibitor of mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase kinase 1. An in vitro kinase assay with Elk-1 as substrate showed that MAPK is activated under hypoxia. The activation of MAPK corresponds temporally with the phosphorylation and activation of Elk-1. Thus, a decrease of the intracellular reactive oxygen intermediate level by hypoxia induces c-fos via the MAPK pathway. These results suggest that the intracellular redox levels may be directly coupled to tumor growth, invasion, and metastasis via Elk-1-dependent induction of c-Fos controlled genes.
AuthorsJ M Müller, B Krauss, C Kaltschmidt, P A Baeuerle, R A Rupec
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 272 Issue 37 Pg. 23435-9 (Sep 12 1997) ISSN: 0021-9258 [Print] United States
PMID9287359 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • DNA-Binding Proteins
  • ELK1 protein, human
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-fos
  • Transcription Factors
  • ets-Domain Protein Elk-1
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Oxygen
Topics
  • Anaerobiosis
  • Calcium-Calmodulin-Dependent Protein Kinases (metabolism)
  • DNA-Binding Proteins
  • Enzyme Activation
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Mitogen-Activated Protein Kinase 1
  • Oxidation-Reduction
  • Oxygen (pharmacology)
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Binding
  • Proto-Oncogene Proteins (metabolism)
  • Proto-Oncogene Proteins c-fos (biosynthesis, genetics)
  • Signal Transduction
  • Transcription Factors (biosynthesis, genetics)
  • Transcription, Genetic (drug effects)
  • ets-Domain Protein Elk-1

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