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.