title: MicroRNA miR-199a* regulates the MET proto-oncogene and the downstream extracellular signal-regulated kinase 2 (ERK2).
abstract: MicroRNAs (miRNAs) constitute a class of small noncoding RNAs that play important roles in a variety of biological processes including development, apoptosis, proliferation, and differentiation. Here we show that the expression of miR-199a and miR-199a* (miR-199a/a*), which are processed from the same precursor, is confined to fibroblast cells among cultured cell lines. The fibroblast-specific expression pattern correlated well with methylation patterns: gene loci on chromosome 1 and 19 were fully methylated in all examined cell lines but unmethylated in fibroblasts. Transfection of miR-199a and/or -199a* mimetics into several cancer cell lines caused prominent apoptosis with miR-199a* being more pro-apoptotic. The mechanism underlying apoptosis induced by miR-199a was caspase-dependent, whereas a caspase-independent pathway was involved in apoptosis induced by miR-199a* in A549 cells. By employing microarray and immunoblotting analyses, we identified the MET proto-oncogene as a target of miR-199a*. Studies with a luciferase reporter fused to the 3'-untranslated region of the MET gene demonstrated miR-199a*-mediated down-regulation of luciferase activity through a binding site of miR-199a*. Interestingly, extracellular signal-regulated kinase 2 (ERK2) was also down-regulated by miR-199a*. Coordinated down-regulation of both MET and its downstream effector ERK2 by miR-199a* may be effective in inhibiting not only cell proliferation but also motility and invasive capabilities of tumor cells.
authors.affiliation: Gene2Drug Research Center, Bioneer Corporation, and National Genome Information Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Seonhoe
authors.initials: S
authors.lastname: Kim
authors.forename: Ui Jin
authors.initials: UJ
authors.lastname: Lee
authors.forename: Mi Na
authors.initials: MN
authors.lastname: Kim
authors.forename: Eun-Ju
authors.initials: EJ
authors.lastname: Lee
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Mi Young
authors.initials: MY
authors.lastname: Lee
authors.forename: Sorim
authors.initials: S
authors.lastname: Choung
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Kim
authors.forename: Young-Chul
authors.initials: YC
authors.lastname: Choi
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004247:DNA / Q000737:chemistry; D019175:DNA Methylation; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D012313:RNA / Q000737:chemistry
chemical_list: C000715470:MAS1 protein, human; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; D012313:RNA; D004247:DNA; D019859:Proto-Oncogene Proteins c-met; D019950:Mitogen-Activated Protein Kinase 1