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J. Biol. Chem., Vol. 279, Issue 46, 47912-47928, November 12, 2004

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Basic Fibroblast Growth Factor-induced Cell Death Is Effected through Sustained Activation of p38^MAPK and Up-regulation of the Death Receptor p75^NTR*

Andrew J. K. Williamson, Benjamin C. Dibling, James R. Boyne, Peter Selby, and Susan A. Burchill¶

From the Candlelighter's Children's Cancer Research Laboratory, Cancer Research UK Clinical Centre, St. James's University Hospital, Leeds LS9 7TF, United Kingdom

Basic fibroblast growth factor (bFGF) induces cell death in cells of the Ewing's sarcoma family of tumors in vivo and in vitro. In this study we demonstrate that this is dependent on the rapid and sustained activation of p38^MAPK, in contrast to the transient activation of p38^MAPK associated with bFGF-induced cell proliferation. Stem cell factor-induced survival of TC-32 cells was also associated with transient activation of p38^MAPK. Inhibition of p38^MAPK by SB202190 and p38^MAPK small interfering RNA reduces bFGF-induced death in TC-32 cells, consistent with the hypothesis that activation of p38^MAPK is essential for induction of death by bFGF. This appears to be dependent on sustained activation of p38^MAPK, demonstrated by inhibition of bFGF-induced cell death following addition of SB202190 to TC-32 cells 5 min after exposure to bFGF (20 ng/ml) and activation of p38^MAPK. Prolonged activation of p38^MAPK is accompanied by a rapid and sustained phosphorylation of Ras and ERK; inhibition of ERK phosphorylation using the MEK-1 inhibitor PD98059 rescued 30% of cells from bFGF-induced death suggesting ERK plays a secondary role in the induction of death. This hypothesis is supported by observations in the A673 cell line; bFGF induced sustained activation of ERK and transient activation of p38^MAPK, which was not associated with cell death. These data demonstrate that sustained activation of p38^MAPK is essential for activation of the death cascade following exposure of Ewing's sarcoma family of tumors cells to bFGF and provide evidence that activation of p38^MAPK results in an up-regulation of the death receptor p75^NTR.

Received for publication, August 6, 2004

^* This work was supported by The Candlelighter's Trust, Leeds, UK. 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.

Both authors contributed equally to this paper.

Present address: The Ben May Institute for Cancer Research, University of Chicago, 924 E. 56th St., Chicago, IL 60637.

^¶ To whom correspondence should be addressed: Cancer Research UK Clinical Centre, St James's University Hospital, Beckett St., Leeds LS9 7TF, UK. Tel.: 44-113-2065873; Fax: 44-113-2429886; E-mail: S.A.Burchill{at}leeds.ac.uk.

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