on December 22, 2005
Published online before print December 22, 2005, doi: 10.1161/01.ATV.0000201042.00725.84
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Submitted on November 2, 2005
Accepted on December 7, 2005
Identification of the cAMP-Responsive Enhancer of the Murine ABCA1 Gene. Requirement for CREB1 and STAT3/4 Elements
Wilfried Le Goff ;
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.
* To whom correspondence should be addressed. 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.
Key words: ABCA1 • cAMP response element • chromatin immunoprecipitation • gene • transcription factor
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