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Molecular and Cellular Biology, April 2008, p. 2528-2548, Vol. 28, No. 8
0270-7306/08/$08.00+0     doi:10.1128/MCB.00784-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Critical Role for Transcription Factor C/EBP-β in Regulating the Expression of Death-Associated Protein Kinase 1 ^,

Padmaja Gade, Sanjit K. Roy, Hui Li, Shreeram C. Nallar, and Dhananjaya V. Kalvakolanu^*

Department of Microbiology and Immunology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201

Received 3 May 2007/ Returned for modification 3 August 2007/ Accepted 22 January 2008

Transcription factor C/EBP-β regulates a number of physiological responses. During an investigation of the growth-suppressive effects of interferons (IFNs), we noticed that cebpb^–/– cells fail to undergo apoptosis upon gamma IFN (IFN-) treatment, compared to wild-type controls. To examine the basis for this response, we have performed gene expression profiling of isogenic wild-type and cebpb^–/– bone marrow macrophages and identified a number of IFN--regulated genes that are dependent on C/EBP-β for their expression. These genes are distinct from those regulated by the JAK-STAT pathways. Genes identified in this screen appear to participate in various cellular pathways. Thus, we identify a new pathway through which the IFNs exert their effects on cellular genes through C/EBP-β. One of these genes is death-associated protein kinase 1 (dapk1). DAPK1 is critical for regulating the cell cycle, apoptosis, and metastasis. Using site-directed mutagenesis, RNA interference, and chromatin immunoprecipitation assays, we show that C/EBP-β binds to the promoter of dapk1 and is required for the regulation of dapk1. Both mouse dapk1 and human dapk1 exhibited similar dependences on C/EBP-β for their expression. The expression of the other members of the DAPK family occurred independently of C/EBP-β. Members of the C/EBP family of transcription factors other than C/EBP-β did not significantly affect dapk1 expression. We identified two elements in this promoter that respond to C/EBP-β. One of these is a consensus C/EBP-β-binding site that constitutively binds to C/EBP-β. The other element exhibits homology to the cyclic AMP response element/activating transcription factor binding sites. C/EBP-β binds to this site in an IFN--dependent manner. Inhibition of ERK1/2 or mutation of an ERK1/2 site in the C/EBP-β protein suppressed the IFN--induced response of this promoter. Together, our data show a critical role for C/EBP-β in a novel IFN-induced cell growth-suppressive pathway via DAPK1.

Published ahead of print on 4 February 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

P.G. and S.K.R. contributed equally to this study.

Present address: Institute of Medical Virology, Wuhan University, Wuhan, Hubei, People's Republic of China.

This article has been cited by other articles:

• Li, H., Gade, P., Nallar, S. C., Raha, A., Roy, S. K., Karra, S., Reddy, J. K., Reddy, S. P., Kalvakolanu, D. V. (2008). The Med1 Subunit of Transcriptional Mediator Plays a Central Role in Regulating CCAAT/Enhancer-binding Protein-{beta}-driven Transcription in Response to Interferon-{gamma}. J. Biol. Chem. 283: 13077-13086 [Abstract] [Full Text]