title: miR-17 extends mouse lifespan by inhibiting senescence signaling mediated by MKP7.
abstract: Here we show that transgenic expression of miR-17 extends lifespan and inhibits cellular senescence. We propose that miR-17 acts as a critical regulator of cellular senescence and tumorigenesis. We demonstrate that miR-17 targets both ADCY5 and IRS1, upregulating the downstream signals MKP7, FoxO3, LC3B, and HIF1α, and downregulating mTOR, c-myc, cyclin D1, and JNK. Silencing either ADCY5 or IRS1 promoted autophagy and repressed cellular senescence and apoptosis. Repression of ADCY5 by miR-17 translocated membrane-bound RGS2 into the nucleus, promoting interactions of RGS2 with HIF1α and the MKP7 promoter, enhancing MKP7 transcription. ADCY5 repression by miR-17 also facilitated the translocation of EGFR and MKP7 from membrane into cytoplasmic and mitochondrial fractions. Importantly, we found that MKP7 inhibited senescence by dephosphorylating PRAS40 at Thr246 and mTOR at Ser2248, facilitating the interaction and loss of function of both molecules. Thus, the oncogenic miR-17 also acts pleiotropically to inhibit cellular senescence and extend longevity.
authors: 1] Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
authors: W W
authors: WW
authors: Du
authors: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.
authors: W
authors: W
authors: Yang
authors: 1] Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
authors: L
authors: L
authors: Fang
authors: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.
authors: J
authors: J
authors: Xuan
authors: 1] Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
authors: H
authors: H
authors: Li
authors: 1] Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
authors: A
authors: A
authors: Khorshidi
authors: 1] Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
authors: S
authors: S
authors: Gupta
authors: 1] Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada [3] Guangdong Institute of Microbiology, Guangzhou, China.
authors: X
authors: X
authors: Li
authors: 1] Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
authors: B B
authors: BB
authors: Yang
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016922:Cellular Senescence; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D008136:Longevity; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D035683:MicroRNAs; C543614:Mirn17 microRNA, mouse; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054637:Dual-Specificity Phosphatases; C438002:Dusp16 protein, mouse; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V