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Originally published In Press as doi:10.1074/jbc.M701983200 on April 26, 2007

J. Biol. Chem., Vol. 282, Issue 25, 18613-18624, June 22, 2007
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Transcriptional Regulation of Cidea, Mitochondrial Cell Death-inducing DNA Fragmentation Factor {alpha}-Like Effector A, in Mouse Liver by Peroxisome Proliferator-activated Receptor {alpha} and {gamma}*

Navin Viswakarma, Songtao Yu, Swati Naik, Papreddy Kashireddy, Kojiro Matsumoto, Joy Sarkar, Sailesh Surapureddi, Yuzhi Jia, M. Sambasiva Rao, and Janardan K. Reddy1

From the Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611-3008

Cidea (cell death-inducing DNA fragmentation factor {alpha}-like effector A), a member of a novel family of proapoptotic proteins, is expressed abundantly in the brown adipose tissue of the mouse. Although Cidea mRNA is not detectable in the mouse liver, we now show that peroxisome proliferator-activated receptor (PPAR) {alpha} ligands Wy-14,643 and ciprofibrate increase the Cidea mRNA level in a PPAR{alpha}-dependent manner, whereas Cidea induction in liver by PPAR{gamma} overexpression is PPAR{alpha} independent. Increase in Cidea mRNA content in liver did not alter the expression of uncoupling protein 1 (Ucp1) gene, which regulates thermogenesis, lipolysis, and conservation of energy. Although Cidea is considered to be a proapoptotic factor, Cidea induction in liver did not result in increased apoptosis. To elucidate the mechanism by which PPAR{alpha} and PPAR{gamma} regulate Cidea gene expression in the liver, we analyzed the promoter region of the Cidea gene. Three putative peroxisome proliferator response elements (PPREs) are found in the Cidea gene promoter. Transactivation, gel-shift, and chromatin immunoprecipitation assays indicated that the proximal PPRE in Cidea gene (Cidea-PPRE1 at -680/-668) is functional for both PPAR{alpha} and -{gamma}. We conclude that Cidea is a novel target gene for both PPAR{alpha} and -{gamma} in the liver where these two transcription factors utilize the same PPRE region for dual regulation. The induction of Cidea in liver with these PPAR{alpha} and -{gamma} agonists suggests a possible role for Cidea in energy metabolism and a less likely role in hepatocyte apoptosis.


Received for publication, March 7, 2007 , and in revised form, April 26, 2007.

* This work was supported in part by National Institutes of Health Grants GM23750 (to J. K. R.) and CA104578 (to J. K. R.) and by the Mayberry Endowment Fund. 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.

1 To whom correspondence should be addressed. Tel.: 312-503-7948; E-mail: jkreddy{at}northwestern.edu.


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