title: let-7-repressesed Shc translation delays replicative senescence.
abstract: The p66Shc adaptor protein is an important regulator of lifespan in mammals, but the mechanisms responsible are still unclear. Here, we show that expression of p66Shc, p52Shc, and p46Shc is regulated at the post-transcriptional level by the microRNA let-7a. The levels of let-7a correlated inversely with the levels of Shc proteins without affecting Shc mRNA levels. We identified 'seedless' let-7a interaction elements in the coding region of Shc mRNA; mutation of the 'seedless' interaction sites abolished the regulation of Shc by let-7a. Our results further revealed that repression of Shc expression by let-7a delays senescence of human diploid fibroblasts (HDFs). In sum, our findings link let-7a abundance to the expression of p66Shc, which in turn controls the replicative lifespan of HDFs.
authors.affiliation: Department of Biochemistry and Molecular Biology, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Xu
authors.forename: Lijun
authors.initials: L
authors.lastname: Pang
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Cai
authors.forename: Xinwen
authors.initials: X
authors.lastname: Liu
authors.forename: Shuai
authors.initials: S
authors.lastname: Yuan
authors.forename: Xiuqin
authors.initials: X
authors.lastname: Fan
authors.forename: Bin
authors.initials: B
authors.lastname: Jiang
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
authors.forename: Yali
authors.initials: Y
authors.lastname: Dou
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
authors.forename: Wengong
authors.initials: W
authors.lastname: Wang
mesh_terms: D016922:Cellular Senescence / Q000235:genetics*; D004171:Diploidy; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D016366:Open Reading Frames / Q000235:genetics; D011485:Protein Binding; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D055765:Shc Signaling Adaptor Proteins / Q000096:biosynthesis* / Q000235:genetics; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C487931:mirnlet7 microRNA, human
keywords: cellular lifespan; let-7a; p66Shc; replicative senescence; translational regulation