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J. Biol. Chem., Vol. 282, Issue 37, 27478-27492, September 14, 2007

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Regulation of Mouse Slo Gene Expression

MULTIPLE PROMOTERS, TRANSCRIPTION START SITES, AND GENOMIC ACTION OF ESTROGEN^*

Pallob Kundu¹, Abderrahmane Alioua, Enrico Stefani^¶, and Ligia Toro^¶||

From the Department of Anesthesiology, Division of Molecular Medicine, the ^||Department of Molecular and Medical Pharmacology and Department of Physiology, ^¶Cardiovascular Research Laboratories and Brain Research Institute, UCLA, Los Angeles, California 90095

The large conductance, voltage- and Ca²⁺-activated K⁺ channel plays key roles in diverse body functions influenced by estrogen, including smooth muscle and neural activities. In mouse (m), estrogen up-regulates the transcript levels of its pore-forming -subunit (Slo, KCNMA1), yet the underlying genomic mechanism(s) is (are) unknown. We first mapped the promoters and regulatory motifs within the mSlo 5'-flanking sequence to subsequently identify genomic regions and mechanisms required for estrogen regulation. mSlo gene has at least two TATA-less promoters with distinct potencies that may direct mSlo transcription from multiple transcription start sites. These qualities mark mSlo as a prototype gene with promoter plasticity capable of generating multiple mRNAs and the potential to adapt to organismal needs. mSlo promoters contain multiple estrogen-responsive sequences, e.g. two quasi-perfect estrogen-responsive elements, ERE1 and ERE2, and Sp1 sites. Accordingly, mSlo promoter activity was highly enhanced by estrogen and blocked by estrogen antagonist ICI 182,780. When promoters are embedded in a 4.91-kb backbone, estrogen responsiveness involves a classical genomic mechanism, via ERE1 and ERE2, that may be complemented by Sp factors, particularly Sp1. Simultaneous but not individual ERE1 and ERE2 mutations caused significant loss of estrogen action. ERE2, which is closer to the proximal promoter, up-regulates this promoter via a classical genomic mechanism. ERE2 strategic position together with ERE1 and ERE2 independence and Sp contribution should ensure mSlo estrogen responsiveness. Thus, the mSlo gene seems to have uniquely evolved to warrant estrogen regulation. Estrogen-mediated mSlo genomic regulation has important implications on long term estrogenic effects affecting smooth muscle and neural functions.

Received for publication, June 11, 2007 , and in revised form, July 13, 2007.

^* This work was supported by National Institutes of Health Grants HL54970 (to L. T.) and HD046510 (to E. S.). 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 Figs. 1 and 2.

¹ To whom correspondence should be addressed: Dept. of Anesthesiology, UCLA, BH-509A CHS, P.O. Box 957115, Los Angeles, CA 90095-7115. Tel.: 310-794-7809; Fax: 310-825-5379; E-mail: pallob{at}ucla.edu.

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