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J. Biol. Chem., Vol. 280, Issue 33, 29533-29542, August 19, 2005

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MAPK-mediated Phosphorylation of GATA-1 Promotes Bcl-X_L Expression and Cell Survival^*

Yung-Luen Yu, Yun-Jung Chiang, Yu-Chun Chen, Michael Papetti¶||, Chiun-Gung Juo, Arthur I. Skoultchi¶**, and Jeffrey J. Y. Yen

From the Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 11529, and the ^¶Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461

In the interleukin 3-dependent hematopoietic cell line Ba/F3, inhibition of mitogen-activated protein kinase, a member of the MAPK/c-Jun N-terminal kinase/stress-activated protein kinase kinase family that plays an important role in cell growth and death control, rapidly leads to severe apoptosis. However, most of the antiapoptotic substrates of MAPK remain to be identified. Here we report that, upon interleukin-3 stimulation of Ba/F3 cells, the transcription factor GATA-1 is strongly phosphorylated at residue serine 26 by a MAPK-dependent pathway. Phosphorylation of GATA-1 increases GATA-1-mediated transcription of the E4bp4 survival gene without significantly changing the DNA-binding affinity of GATA-1. Further characterization of GATA-1 phosphorylation site mutants revealed that the antiapoptotic function of GATA-1 is strongly dependent upon its phosphorylation at the Ser-26 position and is probably mediated through its up-regulation of Bcl-X_L expression. Taken together, our data demonstrate that MAPK-dependent GATA-1 phosphorylation is important for its transactivation of the E4bp4 gene, Bcl-X_L expression and cell survival. Therefore, GATA-1 may represent a novel MAPK substrate that plays an essential role in a cytokine-mediated antiapoptotic response.

Received for publication, June 15, 2005

^* This work was supported in part by an intramural fund from Academia Sinica and by National Science Council of Taiwan Grants NSC-91-2320-B-001-046 and NSC92-2320-B-001-039 (to J. J. Y. Y.). 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.

The on-line version of this article (available at http://www.jbc.org) contains an additional four figures and one table.

Supported by National Health Research Institutes of Taiwan Post-doctoral Fellowship Award PD9201.

^|| Supported by National Institutes of Health Fellowship HL077242-01.

^** Supported by National Institutes of Health Grant HL78381-30.

To whom correspondence should be addressed: Institute of Biomedical Sciences, Academia Sinica. No. 128, Sec. 2, Yen-Jiou-Yuan Rd., Taipei, Taiwan 11529. Tel.: 886-2-2652-3077; Fax: 886-2-2782-9142; E-mail: bmjyen{at}ibms.sinica.edu.tw.

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