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J. Biol. Chem., Vol. 282, Issue 50, 36463-36473, December 14, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/50/36463    most recent M705789200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted 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 Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ren, Y. Articles by Wu, J. Search for Related Content PubMed PubMed Citation Articles by Ren, Y. Articles by Wu, J. Social Bookmarking                      What's this?

Shp2^E76K Mutant Confers Cytokine-independent Survival of TF-1 Myeloid Cells by Up-regulating Bcl-X_L^*

Yuan Ren, Zhengming Chen, Liwei Chen, Nicholas T. Woods, Gary W. Reuther^¶, Jin Q. Cheng^¶, Hong-gang Wang^¶, and Jie Wu^¶1

From the Molecular Oncology Program and the Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute and the ^¶Department of Interdisciplinary Oncology, University of South Florida, Tampa, Florida 33612

Shp2 has been known to mediate growth factor-stimulated cell proliferation, but its role in cell survival is less clear. Gain-of-function Shp2 mutants such as Shp2^E76K are associated with myeloid leukemias. We found that Shp2^E76K could transform cytokine-dependent human TF-1 myeloid cells into cytokine independence and further characterized the Shp2^E76K-induced cell survival mechanism in this study. Expression of Shp2^E76K suppressed the cytokine withdrawal-induced intrinsic/mitochondrial apoptosis pathway, which is controlled by the Bcl-2 family proteins. Analysis of Bcl-2 family proteins showed that Bcl-X_L and Mcl-1 were up-regulated in Shp2^E76K-transformed TF-1 (TF-1/Shp2^E76K) cells. Knockdown of Bcl-X_L but not Mcl-1 with short hairpin RNAs prevented Shp2^E76K-induced cytokine-independent survival. Roscovitine, which down-regulated Mcl-1, also did not prevent cytokine-independent survival of TF-1/Shp2^E76K cells, whereas the Bcl-X_L inhibitor HA14-1 did. Ras and mitogen-activated protein kinases Erk1 and Erk2 (Erk1/2) were constitutively activated in TF-1/Shp2^E76K cells, whereas little active Akt was detected under cytokine-free conditions. Shp2^E76K-induced Bcl-X_L expression was suppressed by Mek inhibitors and by a dominant-negative Mek1 mutant but not by the phosphoinositide 3-phosphate inhibitor LY294002 and the Akt inhibitor API-2. Inhibition of Erk1/2 blocked cytokine-independent survival of TF-1/Shp2^E76K cells, whereas inhibition of Akt had a minimal effect on cytokine-independent survival of TF-1/Shp2^E76K cells. These results show that Shp2^E76K can evoke constitutive Erk1/2 activation in TF-1 cells. Furthermore, Shp2^E76K induces cytokine-independent survival of TF-1 cells by a novel mechanism involving up-regulation of Bcl-X_L through the Erk1/2 pathway.

Received for publication, July 16, 2007 , and in revised form, October 17, 2007.

^* This work was supported in part by National Institutes of Health Grants R01CA077467 and P01CA118210 and a research grant from Children's Leukemia Research Association. 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 To whom correspondence should be addressed: Molecular Oncology Program, SRB-3, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL 33612. Tel.: 813-745-6713; Fax: 813-745-3829; E-mail: jerry.wu{at}moffitt.org.

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