Mitogen-activated protein kinase phosphatase-1 (MKP-1) expression is induced by low oxygen conditions found in solid tumor microenvironments - A candidate MKP for the inactivation of hypoxia-inducible stress-activated protein kinase/c-Jun N-terminal protein kinase activity

Pathophysiological hypoxia is an important modulator of gene expression in solid tumors and other pathologic conditions. We observed that transcriptio nal activation of the c-jun proto oncogene in hypoxic tumor cells correlate s with phosphorylation of the ATF2 transcription factor. This finding sugge sted that hypoxic signals transmitted to c-jun involve protein kinases that target AP-1 complexes (c-Jun and ATF2) that bind to its promoter region, S tress-inducible protein kinases capable of activating c-jun expression incl ude stress-activated protein kinase/c-Jun N-terminal protein kinase (SAPK/J NK) and p38 members of the mitogen-activated protein kinase (MAPK) superfam ily of signaling molecules. To investigate the potential role of MAPKs in t he regulation of c-jun by tumor hypoxia, we focused on the activation SAPK/ JNKs in SiHa human squamous carcinoma cells. Here, we describe the transien t activation of SAPK/JNKs by tumor-like hypoxia, and the concurrent transcr iptional activation of MKP-1, a stress-inducible member of the MAPK phospha tase (MKP) family of dual specificity protein-tyrosine phosphatases. MKP-1 antagonizes SAPK/JNK activation in response to diverse environmental stress es. Together, these findings identify MKP-1 as a hypoxia-responsive gene an d suggest a critical role in the regulation of SAPK/JNK activity in the tum or microenvironment.