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J Biol Chem, Vol. 274, Issue 18, 12890-12897, April 30, 1999

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

Keith R. Laderoute, Holly L. Mendonca, Joy M. Calaoagan, A. Merrill Knapp, Amato J. Giaccia^¶, and Philip J. S. Stork

From the  Pharmaceutical Discovery Division, SRI International, Menlo Park, California 94025, the ^¶ Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305, and the  Vollum Institute and Department of Pathology, Oregon Health Sciences University, Portland, Oregon 97201

Pathophysiological hypoxia is an important modulator of gene expression in solid tumors and other pathologic conditions. We observed that transcriptional activation of the c-jun proto-oncogene in hypoxic tumor cells correlates with phosphorylation of the ATF2 transcription factor. This finding suggested 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. Stress-inducible protein kinases capable of activating c-jun expression include stress-activated protein kinase/c-Jun N-terminal protein kinase (SAPK/JNK) and p38 members of the mitogen-activated protein kinase (MAPK) superfamily of signaling molecules. To investigate the potential role of MAPKs in the regulation of c-jun by tumor hypoxia, we focused on the activation SAPK/JNKs in SiHa human squamous carcinoma cells. Here, we describe the transient activation of SAPK/JNKs by tumor-like hypoxia, and the concurrent transcriptional activation of MKP-1, a stress-inducible member of the MAPK phosphatase (MKP) family of dual specificity protein-tyrosine phosphatases. MKP-1 antagonizes SAPK/JNK activation in response to diverse environmental stresses. Together, these findings identify MKP-1 as a hypoxia-responsive gene and suggest a critical role in the regulation of SAPK/JNK activity in the tumor microenvironment.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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