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J. Biol. Chem., Vol. 283, Issue 38, 25774-25785, September 19, 2008

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Distinct Functions of CCAAT Enhancer-binding Protein Isoforms in the Regulation of Manganese Superoxide Dismutase during Interleukin-1β Stimulation^*

Xiaolei Qiu, Kimberly J. Aiken^¶, Ann L. Chokas^¶, Dawn E. Beachy^¶, and Harry S. Nick^¶1

From the ^¶Department of Neuroscience, McKnight Brian Institute, and Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32610

The mitochondrial antioxidant enzyme manganese superoxide dismutase (Mn-SOD) is crucial in maintaining cellular and organismal homeostasis. Mn-SOD expression is tightly regulated in a manner that synchronizes its cytoprotective functions during inflammatory challenges. Induction of Mn-SOD gene expression by the proinflammatory cytokine IL-1β is mediated through a complex intronic enhancer element. To identify and characterize the transcription factors required for Mn-SOD enhancer function, a yeast one-hybrid assay was utilized, and two CCAAT enhancer-binding protein (C/EBP) members, C/EBP β and C/EBP , were identified. These two transcription factors responded to IL-1β treatment with distinct expression profiles, different temporal yet inducible interactions with the endogenous Mn-SOD enhancer, and also opposite effects on Mn-SOD transcription. C/EBP β is expressed as three isoforms, LAP* (liver-activating protein), LAP, and LIP (liver-inhibitory protein). Our functional analysis demonstrated that only the full-length C/EBP β/LAP* served as a true activator for Mn-SOD, whereas LAP, LIP, and C/EBP functioned as potential repressors. Finally, our systematic mutagenesis of the unique N-terminal 21 amino acids further solidified the importance of LAP* in the induction of Mn-SOD and emphasized the crucial role of this isoform. Our data demonstrating the physiological relevance of the N-terminal peptide also provide a rationale for revisiting the role of LAP* in the regulation of other genes and in pathways such as lipogenesis and development.

Received for publication, February 13, 2008 , and in revised form, June 3, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL39593 and HL067456 (to H. S. N.). 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: Dept. of Neuroscience, P.O. Box 100244, College of Medicine, University of Florida, Gainesville, FL 32610. Tel.: 352-392-3303; Fax: 352-392-6511; E-mail: hnick{at}ufl.edu.

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