title: MicroRNA-21 is a downstream effector of AKT that mediates its antiapoptotic effects via suppression of Fas ligand.
abstract: MicroRNA-21 (miR-21) is highly up-regulated during hypertrophic and cancerous cell growth. In contrast, we found that it declines in cardiac myocytes upon exposure to hypoxia. Thus, the objective was to explore its role during hypoxia. We show that miR-21 not only regulates phosphatase and tensin homologue deleted on chromosome 10 (PTEN), but also targets Fas ligand (FasL). During prolonged hypoxia, down-regulation of miR-21 proved necessary and sufficient for enhancing expression of both proteins. We demonstrate here for the first time that miR-21 is positively regulated via an AKT-dependent pathway, which is depressed during prolonged hypoxia. Accordingly, hypoxia-induced down-regulation of miR-21 and up-regulation of FasL and PTEN were reversed by activated AKT and reproduced by a dominant negative mutant, wortmannin, or PTEN. Moreover, the antiapoptotic function of AKT partly required miR-21, which was sufficient for inhibition of caspase-8 activity and mitochondrial damage. In consensus, overexpression of miR-21 in a transgenic mouse heart resulted in suppression of ischemia-induced up-regulation of PTEN and FasL expression, an increase in phospho-AKT, a smaller infarct size, and ameliorated heart failure. Thus, we have identified a unique aspect of the function of AKT by which it inhibits apoptosis through miR-21-dependent suppression of FasL.
authors.affiliation: Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103, USA.
authors.forename: Danish
authors.initials: D
authors.lastname: Sayed
authors.forename: Minzhen
authors.initials: M
authors.lastname: He
authors.forename: Chull
authors.initials: C
authors.lastname: Hong
authors.forename: Shumin
authors.initials: S
authors.lastname: Gao
authors.forename: Shweta
authors.initials: S
authors.lastname: Rane
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yang
authors.forename: Maha
authors.initials: M
authors.lastname: Abdellatif
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020413:3' Untranslated Regions; D053222:Fas Ligand Protein; C524940:MIRN21 microRNA, human; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase
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