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J. Biol. Chem., Vol. 279, Issue 51, 53116-53125, December 17, 2004

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Phorbol Ester Treatment of K562 Cells Regulates the Transcriptional Activity of AML1c through Phosphorylation^*

Youhong Zhang, Joseph R. Biggs, and Andrew S. Kraft

From the Hollings Cancer Center, the Medical University of South Carolina, Charleston, South Carolina 29425

We find that phorbol ester (PE) treatment of K562 cells greatly stimulates promoters (T cell receptor , myeloperoxidase, macrophage colony-stimulating factor receptor, and granulocyte macrophage colony-stimulating factor receptor) containing AML1 transcription factor binding sites. This stimulation of AML1c transcriptional activity is mediated by direct phosphorylation of the AML1c molecule on multiple phosphorylation sites. Eleven AML1c (S/T)P sites in the transcriptional activating domain are phosphorylated at a basal level in untreated K562 cells; treatment of the K562 cells with PE results in increased phosphorylation at five of these sites (serines 276, 293, 303, 462, and threonine 300). Mutation of these five sites to alanine inhibits PE-induced transcriptional activity; mutation of the sites to an acidic amino acid, aspartic acid, stimulates constitutive activity. Single mutations in four amino acids or double mutations (serines 276 and 293 or threonine 300 and serine 303) have little effect on AML1c transcriptional activity. Inhibitor assays suggest that the ERK family of protein kinases is activated by PEs to phosphorylate the (S/T)P sites within the AML1c molecule and markedly enhance the transcriptional activity of AML1c.

Received for publication, May 17, 2004 , and in revised form, September 30, 2004.

^* This work was supported by National Institutes of Health Grant CA42533 (to A. S. K.). 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: The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037.

To whom correspondence should be addressed: Hollings Cancer Center, the Medical University of South Carolina, 86 Jonathan Lucas St., Charleston, SC 29425. Tel.: 843-792-8284; Fax: 843-792-9456; E-mail: Kraft{at}musc.edu.

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