title: MIR181A regulates starvation- and rapamycin-induced autophagy through targeting of ATG5.
abstract: Macroautophagy (autophagy herein) is a cellular catabolic mechanism activated in response to stress conditions including starvation, hypoxia and misfolded protein accumulation. Abnormalities in autophagy were associated with pathologies including cancer and neurodegenerative diseases. Hence, elucidation of the signaling pathways controlling autophagy is of utmost importance. Recently we and others described microRNAs (miRNAs) as novel and potent modulators of the autophagic activity. Here, we describe MIR181A (hsa-miR-181a-1) as a new autophagy-regulating miRNA. We showed that overexpression of MIR181A resulted in the attenuation of starvation- and rapamycin-induced autophagy in MCF-7, Huh-7 and K562 cells. Moreover, antagomir-mediated inactivation of endogenous miRNA activity stimulated autophagy. We identified ATG5 as an MIR181A target. Indeed, ATG5 cellular levels were decreased in cells upon MIR181A overexpression and increased following the introduction of antagomirs. More importantly, overexpression of ATG5 from a miRNA-insensitive cDNA construct rescued autophagic activity in the presence of MIR181A. We also showed that the ATG5 3' UTR contained functional MIR181A responsive sequences sensitive to point mutations. Therefore, MIR181A is a novel and important regulator of autophagy and ATG5 is a rate-limiting miRNA target in this effect.
authors: Faculty of Engineering and Natural Sciences, Biological Sciences and Bioengineering Program, Sabanci University, Istanbul, Turkey.
authors: Kumsal Ayse
authors: KA
authors: Tekirdag
authors: Gozde
authors: G
authors: Korkmaz
authors: Deniz Gulfem
authors: DG
authors: Ozturk
authors: Reuven
authors: R
authors: Agami
authors: Devrim
authors: D
authors: Gozuacik
mesh_terms: D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020014:K562 Cells; D008247:Lysosomes / Q000378:metabolism; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D017354:Point Mutation; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; D018076:DNA, Complementary; C477012:MAP1LC3A protein, human; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: ATG5; MTOR; hsa-miR-181a; macroautophagy; mammalian autophagy regulation; microRNA; rapamycin; starvation