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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:527.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Identification of the cAMP-Responsive Enhancer of the Murine ABCA1 Gene

Requirement for CREB1 and STAT3/4 Elements

Wilfried Le Goff; Ping Zheng; Gregory Brubaker; Jonathan D. Smith

From the Department of Cell Biology (WL.G., G.B., J.D.S.), Cleveland Clinic Foundation, Cleveland, Ohio; the Department of Rheumatology (P.Z.), New York University School of Medicine, New York, NY; and the Department of Molecular Medicine (J.D.S.), Case Western Reserve University School of Medicine, Cleveland Ohio.

Correspondence to Jonathan D. Smith, Dept. of Cell Biology NC10, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail smithj4{at}ccf.org

Objective— To determine the mechanism by which expression of the murine ABCA1 gene is highly induced by cAMP analogues.

Methods and Results— ABCA1 mRNA turnover cannot account for its induction by cAMP. Thus cAMP induction of ABCA1 mRNA occurs at a transcriptional level. Shotgun cloning DNA fragments from the murine ABCA1 locus identified a strong cAMP responsive enhancer located in the first intron, which led to 25- to 100-fold cAMP-mediated induction of reporter gene activity. Deletions and mutations of this enhancer led to the identification a cAMP-responsive element (CRE) that was essential for the cAMP induction. Furthermore, the capacity of this CRE site to mediate the cAMP induction required the presence of a STAT3/4 element located 81 bp away. A dominant-negative CREB expression vector inhibited the cAMP induction of ABCA1, demonstrating that CREB was required for cAMP induction of ABCA1 expression in RAW264.7 cells.

Conclusion— Phospho-CREB1 controls the cAMP-mediated induction of murine ABCA1 gene expression through a CRE site acting in cooperation with a nearby STAT element. This CRE site is not conserved in the human ABCA1 gene, explaining why human ABCA1 is not strongly stimulated by cAMP analogs.

The cAMP-responsive enhancer in the murine ABCA1 gene was identified by a shotgun cloning strategy. This enhancer contains 2 required elements, a consensus cAMP-responsive element that binds phospho CREB1, and a nearby element that binds STAT3/4. A dominant-negative CREB expression vector inhibited ABCA1 induction by cAMP analogues.

Key Words: ABCA1 • cAMP response element • chromatin immunoprecipitation • gene expression • transcription factor

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