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J. Biol. Chem., Vol. 283, Issue 14, 9248-9256, April 4, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/14/9248    most recent M707316200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ma, C. Articles by Luo, J. Search for Related Content PubMed PubMed Citation Articles by Ma, C. Articles by Luo, J. Social Bookmarking                      What's this?

Interaction between ERK and GSK3β Mediates Basic Fibroblast Growth Factor-induced Apoptosis in SK-N-MC Neuroblastoma Cells^*

Cuiling Ma, Kimberly A. Bower, Gang Chen, Xianglin Shi^¶, Zun-Ji Ke^||1, and Jia Luo^||2

From the Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Robert C. Byrd Health Sciences Center, Morgantown, West Virginia 26506, the Department of Dermatology, Xijing Hospital, Xi'an 710032, China, the ^¶Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536, and the ^||Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai 200031, China

The Ewing's sarcoma family of tumors (ESFT) includes Ewing's sarcoma (ES), Askin's tumor of the chest wall, and peripheral primitive neuroectodermal tumor. Basic fibroblast growth factor (FGF2) suppresses the growth of ESFT cells and causes their apoptosis. The underlying mechanism is unclear. Using a human peripheral primitive neuroectodermal tumor cell line, SK-N-MC, we demonstrated FGF2 stimulated phosphorylation of ERK1 and ERK2 (pERK1/2) and GSK3β (pGSK3β(Tyr-216)), all of which were primarily retained in the cytoplasm. FGF2 promoted the association between ERK and pGSK3β(Tyr-216). Inhibitors for GSK3β (TDZD and LiCl) and ERK (PD98059) protected cells from FGF2-induced apoptosis. On the other hand, inhibitors of GSK3β, but not PD98059 decreased ERK/pGSK3β(Tyr-216) association and caused a nuclear translocation of pERK1/2. Similarly, expression of a kinase-deficient (K85R) GSK3β or GSK3β-small interfering RNA inhibited FGF2-regulated ERK/pGSK3β(Tyr-216) association and translocated pERK to the nucleus. Both K85R GSK3β and small interfering RNA offered protection against FGF2-induced cell death. In contrast, overexpression of wild-type GSK3β sensitized cells to FGF2 cytotoxicity. Hydrogen peroxide and ethanol enhanced FGF2-stimulated pGSK3β(Tyr-216), ERK/pGSK3β(Tyr-216) association, and cytoplasmic retention of pERK1/2. As a result, they potentiated FGF2-induced cell death. Taken together, our results suggested that FGF2-induced accumulation of pERK1/2 in the cytoplasm is toxic for SK-N-MC cells. The formation of an ERK·GSK3β complex retained pERK1/2 in the cytoplasm. In contrast, disruption of the ERK·GSK3β complex resulted in nuclear translocation of pERK1/2 and offered protection.

Received for publication, August 30, 2007 , and in revised form, February 7, 2008.

^* This work was supported in part by National Institutes of Health Grant AA015407, National Natural Science Foundation of China Grants 30470544, 30471452, and 30570580, and Ministry of Science and Technology of China Grant 2007CB947100. 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.

¹ Supported by the One Hundred Talents Program of the Chinese Academy of Sciences.

² To whom correspondence should be addressed: Dept. of Microbiology, Immunology and Cell Biology, WV University School of Medicine, Morgantown, WV 26506. Tel.: 304-293-7208; Fax: 304-293-7823; E-mail: jluo{at}hsc.wvu.edu.

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