MicroRNA miR-199a* regulates the MET proto-oncogene and the downstream extracellular signal-regulated kinase 2 (ERK2)

被引:185
作者
Kim, Seonhoe [2 ]
Lee, Ui Jin [2 ]
Kim, Mi Na [2 ]
Lee, Eun-Ju [2 ]
Kim, Ji Young [2 ]
Lee, Mi Young [2 ]
Choung, Sorim [2 ]
Kim, Young Joo [1 ]
Choi, Young-Chul [2 ]
机构
[1] Korea Res Inst Biosci & Biotechnol, Natl Genome Informat Ctr, Taejon 306220, South Korea
[2] Bioneer Corp, Gene2Drug Res Ctr, Taejon 306220, South Korea
关键词
D O I
10.1074/jbc.M800186200
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
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 miR199a* may be effective in inhibiting not only cell proliferation but also motility and invasive capabilities of tumor cells.
引用
收藏
页码:18158 / 18166
页数:9
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