ToxSci Advance Access published online on May 3, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl003
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1 Department of Environmental Health, Boston University School of Public Health, Boston, MA, 02118, USA
* To whom correspondence should be addressed. There is growing interest in using peroxisome proliferators-activated receptor
Received January 17, 2006
Accepted April 26, 2006
Systems Toxicology
Activation of Multiple MAP Kinases In Pro/Pre-B Cells by GW7845, a PPAR
Jennifer J. Schlezinger 1 *,
Jessica K. Emberley 2,
and
David H. Sherr 1
Agonist, and their Contribution to GW7845-Induced Apoptosis
2 Department of Microbiology, Boston University School of Medicine, Boston, MA, 02118, USA
Jennifer J. Schlezinger, E-mail: jschlezi{at}bu.edu
Abstract 
(PPAR) agonists as chemotherapeutic agents in hematologic malignancies. PPAR agonists of diverse chemical structure induce apoptosis in several malignant B cell lines. However, PPAR agonists also induce apoptosis in normal B cells. One such agonist, GW7845, rapidly induces apoptosis in early B cells. Understanding the mechanisms of PPAR agonist-induced death is essential to minimizing loss of normal cells during chemotherapy. PPAR agonists influence MAPK cascades in other systems, and MAPKs can be associated with apoptosis. Therefore, we investigated the activation of MAPKs in primary pro-B and cultured pro/pre-B cells and their role in GW7845-induced apoptosis. Treatment of a non-transformed murine pro/pre-B cell line with GW7845 transiently induced the phosphorylation of ERK1/2, but strongly and persistently induced the activation of p38 MAPK and JNK. In primary pro-B cells, p38 MAPK and JNK were activated following treatment with GW7845. Phosphorylation of ATF-2 was induced strongly in both B cell types. In pro/pre-B cells, pre-treatment with the p38 MAPK/JNK inhibitor PD169316 potently suppressed multiple facets of GW7845-induced apoptosis signaling. However, when a series of p38 MAPK and JNK inhibitors were used, only SB202190, also a dual inhibitor, completely suppressed GW7845-induced apoptosis. Inhibitors specific for p38 MAPK and JNK were only partially effective, suggesting that suppression of a single MAPK is not sufficient to inhibit death. The results support the hypothesis that GW7845 initiates an apoptotic pathway in early B cells through the activation of a kinase cascade that includes at least p38 MAPK and JNK.; apoptosis; MAPK.
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