RT Journal Article
SR Electronic
T1 miR-34a inhibits cell proliferation by repressing MEK1 during megakaryocytic differentiation of K562
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.109.063321
DO 10.1124/mol.109.063321
A1 Atsuhiko Ichimura
A1 Yoshinao Ruike
A1 Kazuya Terasawa
A1 Kazuharu Shimizu
A1 Gozoh Tsujimoto
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/03/18/mol.109.063321.abstract
AB Phorbol 12-myristate 13-acetate (PMA) induces megakaryocytic differentiation of the human chronic myelocytic leukemia cell line K562. We examined the potential regulatory role of microRNAs (miRNAs) in this process. Genome-wide expression profiling identified 21 miRNAs that were induced by the treatment of K562 cells with PMA. Among them, the expression of miR-34a, miR-221, and miR-222 was induced in the early stages, and maintained throughout the late stages of differentiation. Cell signaling analysis showed that activation of extracellular signal-regulated protein kinase (ERK) in response to PMA strongly induced miR-34a expression by transactivation via the AP-1 binding site in the upstream region of the miR-34a gene. Reporter gene assays identified mitogen-activated protein kinase kinase 1 (MEK1) as a direct target of miR-34a, and c-fos as a direct target of miR-221/222. Although over-expression of the three miRNAs had little effect on cell differentiation, over-expression of miR-34a significantly repressed the proliferation of K562 cells with a concomitant reduction in MEK1 protein expression. Conversely, a locked nucleic acid probe against miR-34a significantly enhanced the proliferation of PMA-treated K562 cells. Taken together, the results show that PMA activates the MEK-ERK pathway and strongly induces miRNA-34a expression, which in turn inhibits cell proliferation by repressing the expression of MEK1. Thus, the results highlight an important regulatory role for miR-34a in the process of megakaryocytic differentiation, especially in the arrest of cell growth, which is a prerequisite for cells to enter differentiation.The American Society for Pharmacology and Experimental Therapeutics