title: MicroRNA-99 family targets AKT/mTOR signaling pathway in dermal wound healing.
abstract: 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 3'-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.
authors.affiliation: Center for Molecular Biology of Oral Diseases, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.forename: Stéphanie D
authors.initials: SD
authors.lastname: Tymen
authors.forename: Dan
authors.initials: D
authors.lastname: Chen
authors.forename: Zong Juan
authors.initials: ZJ
authors.lastname: Fang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Dragan
authors.initials: D
authors.lastname: Dragas
authors.forename: Yang
authors.initials: Y
authors.lastname: Dai
authors.forename: Phillip T
authors.initials: PT
authors.lastname: Marucha
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zhou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D020405:Dermis / Q000473:pathology*; D039642:Eukaryotic Initiation Factors; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014945:Wound Healing / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; C544266:MIRN100 microRNA, human; C561679:MIRN99 microRNA, human; D035683:MicroRNAs; C558180:Mirn100 microRNA, mouse; C573158:Mirn99 microRNA, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases