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J. Biol. Chem., Vol. 279, Issue 2, 825-830, January 9, 2004

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A Chromatin Immunoprecipitation Screen Reveals Protein Kinase C as a Direct RUNX1 Target Gene^*

Bruce A. Hug¶, Nazia Ahmed, Jonathan A. Robbins||, and Mitchell A. Lazar||**

From the Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, the Department of Pathology and Laboratory Medicine, and ^||The Penn Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6149

RUNX1 (also known as AML1) is a DNA-binding transcription factor that functions as a tumor suppressor and developmental determinant in hematopoietic cells. Target promoters have been identified primarily through the use of differential expression strategies and candidate gene approaches but not biochemical screens. Using a chromatin immunoprecipitation screen, we identified protein kinase C as a direct RUNX1 target gene and demonstrate that endogenous RUNX1 binds the chromatinized protein kinase C promoter of U937 cells. A phylogenetically conserved RUNX1-binding site within the PKC promoter binds RUNX1 in electrophoretic mobility shift analyses and confers RUNX1 responsiveness on a heterologous promoter. Changes in RUNX1 activity affect endogenous protein kinase C expression, and a dominant-negative form of RUNX1 protects U937 cells from apoptotic stimuli previously shown to be dependent on protein kinase C. This protection can be reversed by the ectopic expression of protein kinase C. Together these findings demonstrate that protein kinase C is a direct, downstream target of RUNX1 and links RUNX1 to a myeloid apoptotic pathway.

Received for publication, August 27, 2003 , and in revised form, September 25, 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 may be addressed: University of Pennsylvania School of Medicine, 615 CRB, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104-6149. Tel.: 215-898-3660; Fax: 215-898-5408. ** To whom correspondence may be addressed: University of Pennsylvania School of Medicine, 611 CRB, 415 Curie Boulevard, Philadelphia, PA 19104-6149. Tel.: 215-898-0198; Fax: 215-898-5408. E-mail: lazar{at}mail.med.upenn.edu.

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