Nicotine modulates expression of miR-140*, which targets the 3'-untranslated region of dynamin 1 gene (Dnm1).
Nicotine stimulation regulates expression of a diversity of genes, but the underlying mechanisms are largely unknown. MicroRNAs (miRNAs) are short endogenous RNAs known to post-transcriptionally regulate gene expression. To test our hypothesis that miRNAs could mediate nicotine's effect on gene expression regulation, we profiled miRNA expression to explore to what extent miRNAs are modulated by nicotine. Using a rodent miRNA microarray and rat PC12 cell model, we revealed that nicotine selectively modulates expression of multiple miRNAs, indicating that the miRNA pathway is one of cellular mechanisms involved in gene expression regulated by nicotine. Specifically, we demonstrated that nicotine increases expression of miR-140*, coordinated with the nicotine-augmented expression of its host gene WWP2. Further, we demonstrated that miR-140* targets the 3'-untranslated region of dynamin 1 gene (Dnm1), by direct base-pairing. This targeting represses gene translation in the luciferase reporter assay and induces messenger RNA degradation in Dnm1 expression analysis. Consequently, our data indicate that nicotine regulates Dnm1 expression via the miRNA pathway. Because dynamin 1 has an essential role in synaptic endocytosis in the central nervous system, nicotine-induced miRNA-mediated dynamin 1 expression regulation may illustrate its importance in neural plasticity, which underlies a molecular mechanism of nicotine addiction.
Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA 22911, USA.
Weihua
W
Huang
Ming D
MD
Li
D020413:3' Untranslated Regions / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D045744:Cell Line, Tumor; D034284:Dynamin I / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008156:Luciferases / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D016296:Mutagenesis; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D016716:PC12 Cells; D051381:Rats; D014162:Transfection
D020413:3' Untranslated Regions; D035683:MicroRNAs; D018722:Nicotinic Agonists; D009538:Nicotine; D008156:Luciferases; D034284:Dynamin I