title: Identification of a novel MTOR activator and discovery of a competing endogenous RNA regulating autophagy in vascular endothelial cells.
abstract: MTOR, a central regulator of autophagy, is involved in cancer and cardiovascular and neurological diseases. Modulating the MTOR signaling balance could be of great significance for numerous diseases. No chemical activators of MTOR have been found, and the urgent challenge is to find novel MTOR downstream components. In previous studies, we found a chemical small molecule, 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one (3BDO), that inhibited autophagy in human umbilical vein endothelial cells (HUVECs) and neuronal cells. Here, we found that 3BDO activated MTOR by targeting FKBP1A (FK506-binding protein 1A, 12 kDa). We next used 3BDO to detect novel factors downstream of the MTOR signaling pathway. Activation of MTOR by 3BDO increased the phosphorylation of TIA1 (TIA1 cytotoxic granule-associated RNA binding protein/T-cell-restricted intracellular antigen-1). Finally, we used gene microarray, RNA interference, RNA-ChIP assay, bioinformatics, luciferase reporter assay, and other assays and found that 3BDO greatly decreased the level of a long noncoding RNA (lncRNA) derived from the 3' untranslated region (3'UTR) of TGFB2, known as FLJ11812. TIA1 was responsible for processing FLJ11812. Further experiments results showed that FLJ11812 could bind with MIR4459 targeting ATG13 (autophagy-related 13), and ATG13 protein level was decreased along with 3BDO-decreased FLJ11812 level. Here, we provide a new activator of MTOR, and our findings highlight the role of the lncRNA in autophagy.
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology; School of Life Science; Shandong University; Jinan, China.
authors.forename: Di
authors.initials: D
authors.lastname: Ge
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology; School of Life Science; Shandong University; Jinan, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology; School of Life Science; Shandong University; Jinan, China.
authors.forename: ShuYa
authors.initials: S
authors.lastname: Huang
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology; School of Life Science; Shandong University; Jinan, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Peng
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology; School of Life Science; Shandong University; Jinan, China.
authors.forename: PengChong
authors.initials: P
authors.lastname: Wang
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology; School of Life Science; Shandong University; Jinan, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology; School of Life Science; Shandong University; Jinan, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology; School of Life Science; Shandong University; Jinan, China.
authors.forename: Le
authors.initials: L
authors.lastname: Su
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology; School of Life Science; Shandong University; Jinan, China.
authors.forename: ShangLi
authors.initials: S
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research; Chinese Ministry of Education and Chinese Ministry of Health; Shandong University Qilu Hospital; Jinan, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology; School of Life Science; Shandong University; Jinan, China; Institute of Pathology and Southwest Cancer Center; Third Military Medical University; Chongqing, China.
authors.forename: HsiangFu
authors.initials: H
authors.lastname: Kung
authors.affiliation: Institute of Organic Chemistry; School of Chemistry and Chemical Engineering; Shandong University; Jinan, China.
authors.forename: BaoXiang
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology; School of Life Science; Shandong University; Jinan, China; The Key Laboratory of Cardiovascular Remodeling and Function Research; Chinese Ministry of Education and Chinese Ministry of Health; Shandong University Qilu Hospital; Jinan, China.
authors.forename: JunYing
authors.initials: J
authors.lastname: Miao
mesh_terms: D020413:3' Untranslated Regions; D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000071183:Autophagy-Related Proteins; D004789:Enzyme Activation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D010766:Phosphorylation; D039102:Poly(A)-Binding Proteins / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D000074019:T-Cell Intracellular Antigen-1; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000737:chemistry / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C553471:3-benzyl-5-((2-nitrophenoxy)methyl)dihydrofuran-2(3H)-one; C534291:ATG13 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; C550432:FKBP1A protein, human; D035683:MicroRNAs; D039102:Poly(A)-Binding Proteins; D062085:RNA, Long Noncoding; D000074019:T-Cell Intracellular Antigen-1; C509041:TGFB2 protein, human; C071558:TIA1 protein, human; D053781:Transforming Growth Factor beta2; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D022021:Tacrolimus Binding Proteins; D015107:4-Butyrolactone; D020123:Sirolimus
keywords: ATG13; MIR4459; MTOR activator; TIA1; autophagy; lncRNA