cAMP-response element-binding protein contributes to suppression of the A2A adenosine receptor promoter by mutant huntingtin with expanded polyglutamine residues

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

研究成果: 雜誌貢獻文章同行評審

75 引文 斯高帕斯(Scopus)

摘要

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 A2A 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 A2A-R in PC12 cells and primary striatal neurons. Cotransfection of various promoter constructs of the A2A-R gene and an expression construct of poly(Q)-expanded Htt revealed that the Htt mutant suppressed the core promoter activity of the A2A-R gene. Stimulation of the A2A-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 A2A-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 A2A-R promoter activity. Consistently, an atypical CRE site (TCCAGG) is located in the core promoter region of the A2A-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 A2A-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 A2A-R by inhibiting its core promoter at least partially by preventing CREB binding.

原文英語
頁(從 - 到)14331-14340
頁數10
期刊Journal of Biological Chemistry
280
發行號14
DOIs
出版狀態已發佈 - 四月 8 2005
對外發佈

ASJC Scopus subject areas

  • 生物化學
  • 分子生物學
  • 細胞生物學

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