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MicroRNA-99 Family Targets AKT/mTOR Signaling Pathway in Dermal Wound Healing

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posted on 03.01.2014 by Yi Jin, Stephanie D. Tymen, Dan Chen, Zong Juan Fang, Yan Zhao, Dragan Dragas, Yang Dai, Phillip T. Marucha, Xiaofeng Zhou
Recent studies suggest that microRNAs play important roles in dermal wound healing and microRNA deregulation has been linked with impaired wound repair. Here, using a mouse experimental wound healing model, we identified a panel of 63 differentially expressed microRNAs during dermal wound healing, including members of miR-99 family (miR-99a, miR-99b, miR-100). We further demonstrated that miR-99 family members regulate cell proliferation, cell migration, and AKT/mTOR signaling. Combined experimental and bioinformatics analyses revealed that miR-99 family members regulate AKT/mTOR signaling by targeting multiple genes, including known target genes (e.g., IGF1R, mTOR) and a new target (AKT1). The effects of miR-99 family members on the expression of IGF1R, mTOR and AKT1 were validated at both the mRNA and protein levels. Two adjacent miR-99 family targeting sites were identified in the 39-UTR of the AKT1 mRNA. The direct interaction of miR-100 with these targeting sites was confirmed using luciferase reporter assays. The microRNA-100-directed recruitment of AKT1 mRNA to the RNAi-induced silencing complex (RISC) was confirmed by a ribonucleoprotein-IP assay. In summary, we identified a panel of differentially expressed microRNAs which may play important roles in wound healing. We provide evidence that miR-99 family members contribute to wound healing by regulating the AKT/mTOR signaling.

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Funding

This work was supported in part by National Institutes of Health (NIH) PHS grants (CA139596, DE017686, and GM078426), and supplementary funding from University of Illinois at Chicago Centre for Clinical and Translational Science (UIC CCTS)(UL1RR029879). Y.J. is supported by a NIH T32 training grant (DE018381). D.D. is supported in part by a NIH R25 grant (DE022675).

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© 2013 Jin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. © 2013 by Public Library of Science, PLoS ONE

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PLoS One

Language

en_US

issn

1932-6203

Issue date

01/05/2013

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