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J. Biol. Chem., Vol. 280, Issue 14, 14331-14340, April 8, 2005

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cAMP-response Element-binding Protein Contributes to Suppression of the A_2A Adenosine Receptor Promoter by Mutant Huntingtin with Expanded Polyglutamine Residues^*

Ming-Chang Chiang, Yi-Chao Lee, Chuen-Lin Huang, and Yijuang Chern¶

From the Division of Neuroscience, Institute of Biomedical Sciences, Academia Sinica and Institute of Neuroscience, National Yang Ming University, Taipei 11529, Taiwan

Huntington's disease is a neurodegenerative disease resulting from a CAG (glutamine) trinucleotide expansion in exon 1 of the Huntingtin (Htt) gene. The role of the striatum-enriched A_2A adenosine receptor (A_2A-R) in Huntington's disease has attracted much attention lately. In the present study, we found that expression of mutant Htt with expanded poly(Q) significantly reduced the transcript levels of the endogenous A_2A-R in PC12 cells and primary striatal neurons. Cotransfection of various promoter constructs of the A_2A-R gene and an expression construct of poly(Q)-expanded Htt revealed that the Htt mutant suppressed the core promoter activity of the A_2A-R gene. Stimulation of the A_2A-R using CGS21680 forskolin, and a constitutively active cAMP-response element-binding protein (CREB) mutant elevated the reduced promoter activity of the A_2A-R gene by mutant Htt. Moreover, the effect of CGS was blocked by an A_2A-R-selective antagonist (CSC), two inhibitors of protein kinase A, and two dominant negative mutants of (CREB). The protein kinase A/CREB pathway therefore is involved in regulating A_2A-R promoter activity. Consistently, an atypical CRE site (TCCAGG) is located in the core promoter region of the A_2A-R gene. Electrophoretic gel mobility shift assay and mutational inactivation further demonstrated the functional binding of CREB to the core promoter region and showed that expression of poly(Q)-expanded Htt abolished the binding of CREB to this site. Stimulation of the A_2A-R restored the reduced CREB binding caused by the mutant and concurrently reduced mutant Htt aggregation. Collectively, the poly(Q)-expanded mutant Htt suppressed expression of the A_2A-R by inhibiting its core promoter at least partially by preventing CREB binding.

Received for publication, November 24, 2004 , and in revised form, January 28, 2005.

^* This work was supported by National Science Council Grants NSC93-2321-B-001-012 and NSC93-2320-B001-009, Academia Sinica Grants AS91IBC3PP-B and AS91IMB4PP-B, and the Institute of Biomedical Science, Academia Sinica (CRC grants), Taipei, Taiwan. 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. S-1, S-2, and S-3.

^¶ To whom correspondence should be addressed: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan. Tel.: 886-2-26523913; Fax: 886-2-27829143; E-mail: bmychern{at}ibms.sinica.edu.tw.

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