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J. Biol. Chem., Vol. 278, Issue 47, 47326-47339, November 21, 2003

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Central Role of Fas-associated Death Domain Protein in Apoptosis Induction by the Mitogen-activated Protein Kinase Kinase Inhibitor CI-1040 (PD184352) in Acute Lymphocytic Leukemia Cells in Vitro^*

Xue Wei Meng, Joya Chandra, David Loegering, Keri Van Becelaere, Timothy J. Kottke, Steven D. Gore¶, Judith E. Karp¶, Judy Sebolt-Leopold, and Scott H. Kaufmann||

From the Division of Oncology Research, Mayo Clinic, and Department of Molecular Pharmacology, Mayo Graduate School, Rochester, Minnesota 55905, the Cancer Molecular Sciences Department, Pfizer Global Research and Development, Ann Arbor, Michigan 48105, and The ^¶Sidney Kimmel Johns Hopkins Oncology Center, Baltimore, Maryland 21287

Because the MAPK pathway plays important roles in cell proliferation and inhibition of apoptosis, this pathway has emerged as a potential therapeutic target for solid tumors and leukemia. At the present time there is little information about activation of this pathway and the consequences of its inhibition in acute lymphocytic leukemia cells (ALL). In the present study, constitutive MAPK pathway activation, as evidenced by phosphorylation of ERK1 and ERK2, was observed in 8 of 8 human lymphoid cell lines and 33% (8:24) of pretreatment ALL bone marrows. Inhibition of this pathway by the MEK inhibitors CI-1040 and PD098059 induced apoptosis through a unique pathway involving dephosphorylation and aggregation of Fas-associated death domain protein followed by death receptor-independent caspase-8 activation. Jurkat cell variants lacking Fas-associated death domain protein or procaspase-8 were resistant to CI-1040-induced apoptosis, as were Jurkat or Molt3 cells treated with the O-methyl ester of the caspase-8 inhibitor N-(N-benzyloxycarbonylisoleucylglutamyl) aspartate fluoromethyl ketone. In contrast, CI-1040-induced apoptosis was unaffected by blocking anti-Fas antibody, soluble tumor necrosis factor--related apoptosis-inducing ligand decoy receptor, or transfection with cDNA encoding the anti-apoptotic Bcl-2 family member Mcl-1 or dominant negative caspase-9. Collectively, these results identify the MAPK pathway as a potential therapeutic target in ALL and delineate a mechanism by which MEK inhibition triggers apoptosis in ALL cells.

Received for publication, May 7, 2003 , and in revised form, August 15, 2003.

^* This work was supported in part by National Institutes of Health Grants R01 CA69008 and F32 CA93055. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Dept. of Pediatrics, M. D. Anderson Cancer Center, Houston, TX 77030.

^|| To whom correspondence and reprints should be addressed: Division of Oncology Research, Guggenheim 1342 C, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905. Tel.: 507-284-8950; Fax: 507-284-3906; E-mail: Kaufmann.Scott{at}Mayo.edu.

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