ToxSci Advance Access originally published online on May 3, 2006
Toxicological Sciences 2006 92(2):433-444; doi:10.1093/toxsci/kfl003
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Activation of Multiple Mitogen-Activated Protein Kinases in Pro/Pre–B Cells by GW7845, a Peroxisome Proliferator–Activated Receptor 
Agonist, and Their Contribution to GW7845-Induced Apoptosis
* Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts 02118; and Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts 02118
Received January 17, 2006; accepted April 26, 2006
There is growing interest in using peroxisome proliferator–activated receptor (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 mitogen-activated protein kinase (MAPK) cascades in other systems, and MAPKs can be associated with apoptosis. Therefore, we investigated the activation of MAPKs in primary pro–B cells and cultured pro/pre–B cells and their role in GW7845-induced apoptosis. Treatment of a nontransformed murine pro/pre–B-cell line with GW7845 transiently induced the phosphorylation of extracellular signal–related protein kinase (ERK) 1/2, but strongly and persistently induced the activation of p38 MAPK and c-Jun NH2-terminal kinase (JNK). In primary pro–B-cells, p38 MAPK and JNK were activated following treatment with GW7845. Phosphorylation of activating transcription factor-2 (ATF-2) was induced strongly in both B-cell types. In pro/pre–B cells, pretreatment 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.
Key Words: bone marrow; B cells; PPAR; apoptosis; MAPK.
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