Regulation of Monoamine Oxidase B Gene Expression: Key Roles for Transcription Factors Sp1, Egr1 and CREB, and microRNAs miR-300 and miR-1224

被引:12
作者
Arige, Vikas [1 ]
Agarwal, Anshu [1 ]
Khan, Abrar A. [1 ]
Kalyani, Ananthamohan [1 ]
Natarajan, Bhargavi [1 ]
Gupta, Vinayak [1 ]
Reddy, S. Santosh [2 ,3 ]
Barthwal, Manoj K. [2 ]
Mahapatra, Nitish R. [1 ]
机构
[1] Indian Inst Technol Madras, Bhupat & Jyoti Mehta Sch Biosci, Dept Biotechnol, Chennai 600036, Tamil Nadu, India
[2] CSIR Cent Drug Res Inst, Div Pharmacol, Lucknow 226031, Uttar Pradesh, India
[3] Acad Sci & Innovat Res AcSIR, New Delhi 110025, India
关键词
transcriptional regulation; post-transcriptional regulation; dopamine; cyclic AMP; protein kinase A; DOPAMINE NEURONS; RESPONSE ELEMENT; PROTEIN; ACTIVATION; BRAIN; MPTP; CASCADE; CELLS; NEUROTOXICITY; DYSFUNCTION;
D O I
10.1016/j.jmb.2019.01.042
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Monoamine oxidase B (MAO-B), a flavoenzyme located in the outer mitochondrial membrane, is involved in the catabolism of monoamines. Altered levels of MAO-B are associated with cardiovascular/neuronal diseases. However, molecular mechanisms of MAO-B gene regulation are partially understood. We undertook a systematic analysis of the MAO-B gene to identify the key transcriptional/post-transcriptional regulatory molecules. Expression of MAO-B promoter-reporter constructs in cultured cells identified the -144425-bp domain as the core promoter region. Stringent in silico analysis of this core promoter predicted binding sites for several transcription factors. Overexpression/down-regulation of transcription factors Sp1/Egr1/CREB increased/decreased the MAO-B promoter- reporter activity and endogenous MAO-B protein level. Electrophoretic mobility shift assays and ChIP assays provided evidence for interactions of Sp1/Egr1/CREB with the MAO-B promoter. MAOB transcript level also positively correlated with the transcript level of Sp1/Egr1/CREB in various human tissue samples. Computational predictions using multiple algorithms coupled with systematic functional analysis revealed direct interactions of the microRNAs miR-1224 and miR-300 with MAO-B 3'-UTR. Dopamine dose-dependently enhanced MAO-B transcript and protein levels via increased binding of CREB to MAO-B promoter and reduced miR-1224/miR-300 levels. 8-Bromo-cAMP and forskolin augmented MAO-B expression, whereas inhibition of PKA diminished the gene expression suggesting involvement of cAMP-PKA axis. Interestingly, Sp1/Egr1/CREB/miR-1224 levels correlate with MAO-B expression in rodent models of hypertension/MPTP-induced neurodegeneration, indicating their roles in governing MAO-B gene expression in these disease states. Taken together, this study elucidates the previously unknown roles of the transcription factors Sp1/Egr1/CREB and microRNAs miR-1224/miR-300 in regulating MAO-B gene expression under basal/disease states involving dysregulated catecholamine levels. (C) 2019 Elsevier Ltd. All rights reserved.
引用
收藏
页码:1127 / 1147
页数:21
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