MicroRNA-21 is a downstream effector of AKT that mediates its antiapoptotic effects via suppression of Fas ligand.
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.
Sayed
Danish
D
Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103, USA.
He
Minzhen
M
Hong
Chull
C
Gao
Shumin
S
Rane
Shweta
S
Yang
Zhi
Z
Abdellatif
Maha
M
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
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
Clin Cancer Res. 2008 Jul 15;14(14):4640-9
18628479
Diabetologia. 2007 Feb;50(2):395-403
17195063
J Mol Cell Cardiol. 2009 Jul;47(1):5-14
19336275
J Mol Cell Cardiol. 2003 Oct;35(10):1229-40
14519433
J Biol Chem. 1994 Jun 3;269(22):15423-6
8195182
Am J Physiol Heart Circ Physiol. 2006 May;290(5):H2116-23
16339840
Cancer Res. 2004 Sep 1;64(17):6127-36
15342396
J Biol Chem. 2009 Oct 23;284(43):29514-25
19706597
Brain Res. 2009 Aug 25;1286:13-8
19559015
Circ Res. 2007 Feb 16;100(3):416-24
17234972
Cancer Res. 2008 Mar 1;68(5):1254-60
18296647
J Biol Chem. 1999 Jun 18;274(25):17612-8
10364198
J Biol Chem. 2007 May 11;282(19):14328-36
17363372
Cell Signal. 2010 Jul;22(7):1054-62
20193759
Nature. 2008 Dec 18;456(7224):980-4
19043405
J Neurosci. 2008 Dec 31;28(53):14341-6
19118166
Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2082-7
14769918
Am J Physiol Heart Circ Physiol. 2003 Feb;284(2):H456-63
12414449
J Mol Cell Cardiol. 2009 Feb;46(2):193-200
19038262
Nat Cell Biol. 2008 Aug;10(8):987-93
18604195
Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18255-60
17108080
Mol Cell Biol. 2006 Apr;26(7):2772-81
16537919
Circ Res. 2004 Sep 17;95(6):627-36
15297380
Mol Cell Biol. 2005 Mar;25(6):2498-510
15743841
Cardiovasc Res. 2009 Apr 1;82(1):21-9
19147652
Circ Res. 2007 Jun 8;100(11):1579-88
17478730
Mol Cell Biol. 2002 Jan;22(2):680-91
11756562
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61
16461460
Cell. 2009 May 15;137(4):647-58
19409607
Methods Mol Biol. 1991;7:109-28
21416352
Oncogene. 2008 Apr 3;27(15):2128-36
17968323
Cancer Res. 2008 Oct 1;68(19):7846-54
18829540
Eur Heart J. 2003 Apr;24(8):742-51
12713768
Gastroenterology. 2007 Aug;133(2):647-58
17681183
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2003 Nov;147(1):19-25
15034601
J Biol Chem. 2008 Jan 11;283(2):1026-33
17991735
Oncogene. 1999 Apr 1;18(13):2189-99
10327065
Circ Res. 2009 Mar 13;104(5):572-5
19213952
Br J Pharmacol. 2007 Apr;150(7):833-8
17293884
Mol Cell Biol. 2005 Feb;25(3):1135-45
15657439
J Mol Cell Cardiol. 2007 Jun;42(6):1137-41
17498736
Oncogene. 2008 Sep 18;27(41):5464-76
18794881
Mol Biol Cell. 2008 Aug;19(8):3272-82
18508928
Gastroenterology. 2006 Jun;130(7):2113-29
16762633
Circ Res. 2009 Apr 10;104(7):879-86
19265035
Circ J. 2004 Aug;68(8):747-50
15277733
Am J Pathol. 2007 Jun;170(6):1831-40
17525252