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J. Biol. Chem., Vol. 279, Issue 10, 9400-9408, March 5, 2004

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Bcr-Abl Regulates Protein Kinase C (PKC) Transcription via an Elk1 Site in the PKC Promoter^*

W. Clay Gustafson, Sutapa Ray, Lee Jamieson, E. Aubrey Thompson, Allan R. Brasier, and Alan P. Fields¶

From the Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida 32224 and the Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555

The protein kinase C (PKC) family of serine/threonine kinases plays an important role in numerous cancer signaling pathways, including those downstream of the bcr-abl oncogene. We demonstrated previously that atypical PKC is required for Bcr-Abl-mediated resistance of human K562 chronic myelogenous leukemia (CML) cells to Taxol-induced apoptosis. Here, we report that the pattern of PKC isozyme expression characteristic of CML cells is regulated by Bcr-Abl. When Bcr-Abl was expressed in Bcr-Abl-negative HL-60 promyelocytic leukemia cells, expression of the PKCI, PKCII, and PKC genes was induced, whereas expression of the PKC gene was reduced to levels similar to those found in CML cells. Given the importance of PKC in Bcr-Abl-mediated transformation, we characterized the mechanism by which Bcr-Abl regulates PKC expression. A 1200-bp PKC promoter construct isolated from genomic DNA was highly active in Bcr-Abl-positive K562 cells and was activated when Bcr-Abl-negative cells were transfected with Bcr-Abl. Bcr-Abl-mediated induction of the PKC promoter was dependent upon MEK1/2 activity, but not phosphatidylinositol 3-kinase or p38 MAPK activity. Mutational analysis of the PKC promoter revealed a region between 97 and 114 bp upstream of the transcriptional start site that is responsible for Bcr-Abl-mediated regulation. Mutation of a consensus Elk1-binding site within this region abolished Bcr-Abl-mediated regulation. We conclude that Bcr-Abl regulates PKC expression through the MEK-dependent activation of an Elk1 element within the proximal PKC promoter. Our results indicate that Bcr-Abl-mediated transformation involves transcriptional activation of the PKC gene, which in turn is required for Bcr-Abl-mediated chemoresistance.

Received for publication, November 24, 2003 , and in revised form, December 9, 2003.

^* 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.

^¶ To whom correspondence should be addressed: Mayo Clinic Comprehensive Cancer Center, Griffin Cancer Research Bldg., Rm. 312, 4500 San Pablo Rd., Jacksonville, FL 32224. Tel.: 904-953-6109; Fax: 904-953-0277; E-mail: fields.alan{at}mayo.edu.

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