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J. Biol. Chem. 277 (9): 7587-7597

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Repression of Activator Protein-1-mediated Transcriptional Activation by the Notch-1 Intracellular Domain*

Jianlin ChuDagger §, Shawn Jeffries||, Jason E. NortonDagger ||, Anthony J. Capobianco, and Emery H. BresnickDagger **

From the Dagger  University of Wisconsin Medical School, Department of Pharmacology, Molecular and Cellular Pharmacology Program, Madison, Wisconsin 53706 and  University of Cincinnati College of Medicine, Department of Molecular Genetics, Biochemistry and Microbiology, Cincinnati, Ohio 45267-0524

Developmental decisions that control cell fate are commonly regulated by the Notch signaling pathway. Activation of transmembrane Notch receptors results in proteolytic liberation of the intracellular domain of Notch, which translocates into the nucleus, binds a repressor (C promoter binding factor 1/RBP-Jkappa , Su(H), and Lag-1 (CSL)), and induces target genes. We found that the intracellular domain of human Notch-1 (NIC-1) represses activator protein-1 (AP-1)-mediated transactivation. Because numerous genes that control immune and inflammatory responses are AP-1-dependent and Notch regulates immune cell function, we investigated the underlying molecular mechanisms. Repression of AP-1 by NIC-1 did not represent a general inhibitory effect on transcription because nuclear factor kappa B-dependent transcription and transcription driven by a constitutive promoter and enhancer were not affected by NIC-1. The physiological relevance of the repression was supported by the facts that repression was apparent in multiple cell lines, endogenous AP-1 target genes were repressed, and similar concentrations of NIC-1 were required for CSL-dependent activation and AP-1 repression. The RBP-Jkappa -associated molecule domain of NIC-1 that mediates CSL binding and distinct sequences necessary for transactivation were required for repression. However, there was not a strict correlation between the sequence requirements for CSL-dependent activation and AP-1 repression. Repression correlated with predominant nuclear localization of NIC-1 and was not accompanied by disruption of c-Jun amino-terminal kinase-dependent signaling events required for AP-1 activation or by defective AP-1 DNA binding activity. These results provide evidence for negative cross-talk between Notch and AP-1, which may have important consequences for controlling diverse biological processes.


* This work was supported by the Milwaukee Foundation, the Leukemia Society of America, the American Heart Association-Northland Affiliate, and National Institutes of Health Grant DK50107.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ A predoctoral fellow of the American Heart Association.

|| Both authors contributed equally to this work.

** A Leukemia Society of America Scholar and a Shaw Scientist. To whom correspondence should be addressed: University of Wisconsin Medical School, Dept. of Pharmacology, Molecular and Cellular Pharmacology Program, 387 Medical Sciences Center, 1300 University Ave., Madison, WI 53706. Tel.: 608-265-6446; Fax: 608-262-1257; E-mail: ehbresni@facstaff.wisc.edu.


Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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