Src Regulates the Expression of Lin28: Implications for Cell Growth, Adhesion, and Communication

Khusial, P. Raaj; Vadla, Bhaskar; Goldberg, Gary S.

doi:10.1080/15419060902825980

Cited by 1 publication

(1 citation statement)

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“…In addition to transcription factor (CCAAT-enhancer-binding protein ␣, Myc, etc. )-dependent mechanisms, kinases may regulate miRNA expression through post-transcriptional events, such as that observed with LIN28 (Newman et al, 2008;Khusial et al, 2009). Future studies will aim to determine the mechanism of Lyn-dependent effects on miR181 expression.…”

Section: Discussionmentioning

confidence: 99%

Lyn Kinase-Dependent Regulation of miR181 and Myeloid Cell Leukemia-1 Expression: Implications for Drug Resistance in Myelogenous Leukemia

Zimmerman¹,

Dollins²,

Crawford³

et al. 2010

Molecular Pharmacology

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Imatinib, a BCR-Abl inhibitor, is a successful front-line treatment for chronic myelogenous leukemia (CML). Despite the success of imatinib, multiple mechanisms of resistance remain a problem, including overexpression of Lyn kinase (Lyn) and Bcl-2 family antiapoptotic proteins. Profiling micro-RNA (miRNA) expression in a model of Lyn-mediated imatinibresistant CML (MYL-R) identified approximately 30 miRNAs whose expression differed Ͼ2-fold compared with drugsensitive MYL cells. In particular, the expression of the miR181 family (a-d) was significantly reduced (ϳ11-to 25-fold) in MYL-R cells. Incubation of MYL-R cells with a Lyn inhibitor (dasatinib) or nucleofection with Lyn-targeting short interfering RNA increased miR181b and miR181d expression. A similar Lyn-dependent regulation of miR181b and miR181d was observed in imatinib-resistant K562 CML cells. Sequence analysis of potential targets for miR181 regulation predicted myeloid cell leukemia-1 (Mcl-1), a Bcl-2 family member whose expression is increased in MYL-R cells and drug-resistant leukemias. Inhibition of Lyn or rescue of miR181b expression reduced Mcl-1 expression in the MYL-R cells. To further investigate the mechanism of Mcl-1 repression by miR181, a luciferase reporter construct incorporating the Mcl-1 3Ј-untranslated region was tested. Overexpression of miR181b reduced luciferase activity, whereas these effects were ablated by the mutation of the seed region of the miR181 target site. Finally, stimulation of Lyn expression by 1,25-dihydroxyvitamin D 3 treatment in HL-60 cells, a cell model of acute myelogenous leukemia, decreased miR181b expression and increased Mcl-1 expression. In summary, our results suggest that Lyn-dependent regulation of miR181 is a novel mechanism of regulating Mcl-1 expression and cell survival.

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Section: Discussionmentioning

confidence: 99%