Hypoxia-induced bFGF gene expression is mediated through the JNK signal transduction pathway

Although the synthesis of angiogenic factors in hypoxic regions of solid tu mors is recognized as one of the critical steps in tumor growth and metasta sis, the signal transduction pathway involved in hypoxic induction of basic fibroblast growth factor (bFGF) gene expression is still obscure. In the s tudy described here, we investigated the intracellular responses to hypoxia and the mechanisms triggering the initiation of angiogenic activity in dru g-resistant human breast carcinoma MCF-7/ADR cells. Northern blots showed a n increase in the level of c-jun, c-fos, and bFGF mRNA during hypoxia. Gel mobility-shift analysis of nuclear extracts from hypoxia-exposed cells show ed an increase in AP-1 binding activity. In addition, hypoxic treatment str ongly activated c-Jun N-terminal kinase 1 (JNK1), leading to phosphorylatio n and activation of c-Jun. Expression of a dominant negative mutant of JNK1 suppressed hypoxia-induced JNK1 activation as well as bFGF gene expression . Taken together, hypoxia-induced bFGF gene expression is mediated through the stress-activated protein kinase (SAPK) signal transduction pathway.