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J. Biol. Chem., Vol. 283, Issue 19, 13077-13086, May 9, 2008

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The Med1 Subunit of Transcriptional Mediator Plays a Central Role in Regulating CCAAT/Enhancer-binding Protein-β-driven Transcription in Response to Interferon-^*

Hui Li¹, Padmaja Gade¹, Shreeram C. Nallar, Abhijit Raha, Sanjit K. Roy, Sreenivasu Karra, Janardan K. Reddy, Sekhar P. Reddy^¶, and Dhananjaya V. Kalvakolanu²

From the Department of Microbiology and Immunology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201, the Department of Pathology, Northwestern University School of Medicine, Chicago, Illinois, and the ^¶Department of Environmental Health Sciences, The Johns Hopkins University School of Public Health, Baltimore, Maryland 21205

Transcription factor CCAAT/enhancer-binding protein (C/EBP)-β is crucial for regulating transcription of genes involved in a number of diverse cellular processes, including those involved in some cytokine-induced responses. However, the mechanisms that contribute to its diverse transcriptional activity are not yet fully understood. To gain an understanding into its mechanisms of action, we took a proteomic approach and identified cellular proteins that associate with C/EBP-β in an interferon (IFN)--dependent manner. Transcriptional mediator (Mediator) is a multisubunit protein complex that regulates signal-induced cellular gene transcription from enhancer-bound transcription factor(s). Here, we report that the Med1 subunit of the Mediator as a C/EBP-β-interacting protein. Using gene knock-out cells and mutational and RNA interference approaches, we show that Med1 is critical for IFN-induced expression of certain genes. Med1 associates with C/EBP-β through a domain located between amino acids 125 and 155 of its N terminus. We also show that the MAPK, ERK1/2, and an ERK phosphorylation site within regulatory domain 2, more specifically the Thr¹⁸⁹ residue, of C/EBP-β are essential for it to bind to Med1. Last, an ERK-regulated site in Med1 protein is also essential for up-regulating IFN-induced transcription although not critical for binding to C/EBP-β.

Received for publication, January 23, 2008 , and in revised form, March 3, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants CA78282 (to D. V. K.), CA104578 and GM23750 (to J. K. R.), and ES011863 (to S. P. R.). 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 supplemental Tables 1–3 and Figs. S1–S4.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 410-328-1396; Fax: 410-706-6609; E-mail: dkalvako{at}umaryland.edu.

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