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J. Biol. Chem., Vol. 279, Issue 20, 21021-21028, May 14, 2004

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Dual Functions of Transcription Factors, Transforming Growth Factor--inducible Early Gene (TIEG)2 and Sp3, Are Mediated by CACCC Element and Sp1 Sites of Human Monoamine Oxidase (MAO) B Gene^*

Xiao-Ming Ou, Kevin Chen, and Jean C. Shih¶

From the Department of Molecular Pharmacology and Toxicology, School of Pharmacy and Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033

Monoamine oxidases (MAO) A and B catalyze the oxidative deamination of many biogenic and dietary amines. Abnormal expression of MAO has been implicated in several psychiatric and neurodegenerative disorders. Human MAO B core promoter (-246 to -99 region) consists of CACCC element flanked by two clusters of overlapping Sp1 sites. Here, we show that cotransfection with transforming growth factor (TGF)--inducible early gene (TIEG)2 increased MAO B gene expression at promoter, mRNA, protein, and catalytic activity levels in both SH-SY5Y and HepG2 cells. Mutation of the CACCC element increased the MAO B promoter activity, and cotransfection with TIEG2 further increased the promoter activity, suggesting that CACCC was a repressor element. This increase was reduced when the proximal Sp1 overlapping sites was mutated. Similar interactions were found with Sp3. These results showed that TIEG2 and Sp3 were repressors at the CACCC element but were activators at proximal Sp1 overlapping sites of MAO B. Gel-shift and chromatin immunoprecipitation assays showed that TIEG2 and Sp3 bound directly to CACCC element and the proximal Sp1 sites in both synthetic oligonucleotides and natural MAO B core promoter. TIEG2 had a higher affinity to Sp1 sites than CACCC element, whereas Sp3 had an equal affinity to both elements. Thus, TIEG2 was an activator, but Sp3 had no effect on MAO B gene expression. This study provides new insights into MAO B gene expression and illustrates the complexity of gene regulation.

Received for publication, November 19, 2003 , and in revised form, February 9, 2004.

^* This work was supported by National Institute of Mental Health Grants R01 MH37020 and R37 MH39085 (MERIT Award), the Boyd and Elsie Welin Professorship, and 2002 NARSAD Young Investigator Award. 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.

^¶ To whom correspondence should be addressed: Dept. of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, 1985 Zonal Ave., PSC 528, Los Angeles, CA 90033. Tel.: 323-442-1441; Fax: 323-442-3229; E-mail: jcshih{at}usc.edu.

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