Transcriptional regulation of mouse mu opioid receptor gene in neuronal cells by Poly(ADP-ribose) polymerase-1
Corresponding Author
Hack Sun Choi
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
Correspondence to: Hack Sun Choi, Ph. D.,Department of Pharmacology, University of Minnesota Medical School,6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA.Tel.:+(61 2)62 66 53 9Fax.: +(61 2) 62 58 40 8Email: [email protected]Search for more papers by this authorCheol Kyu Hwang
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
Search for more papers by this authorChun Sung Kim
Department of Oral Physiology and The second stage of BK21, Chosun University College of Dentistry, Korea
Search for more papers by this authorKyu Young Song
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
Search for more papers by this authorPing-Yee Law
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
Search for more papers by this authorHorace H. Loh
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
Search for more papers by this authorLi-Na Wei
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
Search for more papers by this authorCorresponding Author
Hack Sun Choi
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
Correspondence to: Hack Sun Choi, Ph. D.,Department of Pharmacology, University of Minnesota Medical School,6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA.Tel.:+(61 2)62 66 53 9Fax.: +(61 2) 62 58 40 8Email: [email protected]Search for more papers by this authorCheol Kyu Hwang
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
Search for more papers by this authorChun Sung Kim
Department of Oral Physiology and The second stage of BK21, Chosun University College of Dentistry, Korea
Search for more papers by this authorKyu Young Song
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
Search for more papers by this authorPing-Yee Law
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
Search for more papers by this authorHorace H. Loh
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
Search for more papers by this authorLi-Na Wei
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
Search for more papers by this authorAbstract
The pharmacological actions of morphine and morphine-like drugs such as heroin mediate primarily through the mu opioid receptor (MOR). It represents the target of the most valuable painkiller in contemporary medicine. Here we report that poly(ADP-ribose) polymerase 1 (PARP-1) binds to the double-stranded poly(C) element essential for the MOR promoter and represses promoter activity at the transcriptional level. We identified PARP-1 by affinity column chromatography using the double-stranded poly(C) element, followed by two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry. PARP-1 binding to the poly(C) sequence of the MOR gene was sequence-specific as confirmed by the supershift assay. In cotransfection studies, PARP-1 repressed the MOR promoter only when the poly(C) sequence was intact. When PARP-1 was disrupted in NS20Y cells using siRNA, transcription of the endogenous target MOR gene increased significantly. Chromatin immunoprecipitation assays showed specific binding of PARP-1 to the double-stranded poly(C) element essential for the MOR promoter. Inhibition of PARP-1's catalytic domain with 3-aminobenzamide increased endogenous MOR mRNA levels in cultured NS20Y cells, suggesting that automodification of PARP-1 regulates MOR transcription. Our data suggest that PARP-1 can function as a repressor of MOR transcription dependent on the MOR poly(C) sequence. We demonstrate for the first time a role of PARP-1 as a transcriptional repressor in MOR gene regulation.
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