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Molecular and Cellular Biology, April 1999, p. 2547-2555, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Protein-Damaging Stresses Activate c-Jun N-Terminal Kinase via Inhibition of Its Dephosphorylation: a Novel Pathway Controlled by HSP72

Anatoli B. Meriin,1 Julia A. Yaglom,1 Vladimir L. Gabai,1 Dick D. Mosser,2 Leonard Zon,3 and Michael Y. Sherman1,*

Boston Biomedical Research Institute, Boston, Massachusetts 021141; Biotechnology Research Institute, Montreal, Quebec H4P 2R2, Canada2; and Children's Hospital, Boston, Massachusetts 021153

Received 7 October 1998/Returned for modification 14 December 1998/Accepted 6 January 1999

Various stresses activate the c-Jun N-terminal kinase (JNK), which is involved in the regulation of many aspects of cellular physiology, including apoptosis. Here we demonstrate that in contrast to UV irradiation, heat shock causes little or no stimulation of the JNK-activating kinase SEK1, while knocking out the SEK1 gene completely blocks heat-induced JNK activation. Therefore, we tested whether heat shock activates JNK via inhibition of JNK dephosphorylation. The rate of JNK dephosphorylation in unstimulated cells was high, and exposure to UV irradiation, osmotic shock, interleukin-1, or anisomycin did not affect this process. Conversely, exposure of cells to heat shock and other protein-damaging conditions, including ethanol, arsenite, and oxidative stress, strongly reduced the rate of JNK dephosphorylation. Under these conditions, we did not observe any effects on dephosphorylation of the homologous p38 kinase, suggesting that suppression of dephosphorylation is specific to JNK. Together, these data indicate that activation of JNK by protein-damaging treatments is mediated primarily by inhibition of a JNK phosphatase(s). Elevation of cellular levels of the major heat shock protein Hsp72 inhibited a repression of JNK dephosphorylation by these stressful treatments, which explains recent reports of the suppression of JNK activation by Hsp72.

* Corresponding author. Mailing address: Boston Biomedical Research Institute, 20 Staniford St., Boston, MA 02114. Phone: (617) 912-0312. Fax: (617) 912-0308. E-mail: sherman{at}bbri.harvard.edu.

Molecular and Cellular Biology, April 1999, p. 2547-2555, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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