title: HuR maintains a replicative life span by repressing the ARF tumor suppressor.
abstract: p19(ARF) plays an essential role in the senescence of mouse cells, and its expression is lost by methylation or deletion of the ARF locus; otherwise, p53 is inactivated to bypass senescence. ARF expression is tightly regulated, but little is known about its posttranscriptional regulation. Here, we show that an RNA-binding protein, HuR (human antigen R), represses ARF mRNA translation, thereby maintaining the replicative life span of mouse embryonic fibroblasts (MEFs). Loss of HuR results in premature senescence, with concomitant increases in p19(ARF) but not p16(Ink4a) levels, and this senescence is not observed in ARF-null MEFs that retain an intact Ink4a locus. HuR depletion does not alter ARF transcription or stability but enhances ribosome association with ARF mRNA. Under these conditions, ARF mRNA accumulates in nucleoli, where it associates with nucleolin. Furthermore, adipose-specific deletion of the HuR gene results in increased p19(ARF) expression in aged animals, which is accompanied by decreased insulin sensitivity. Together, our findings demonstrate that p19(ARF) is also regulated at the translational level, and this translational regulation restrains the cellular life span and tissue functions in vivo.
authors.affiliation: Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawagishi
authors.forename: Michihiro
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Takayuki
authors.initials: T
authors.lastname: Tsugawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Watanabe
authors.forename: Dimitris L
authors.initials: DL
authors.lastname: Kontoyiannis
authors.forename: Masataka
authors.initials: M
authors.lastname: Sugimoto
mesh_terms: D020121:5' Untranslated Regions; D050156:Adipogenesis; D000818:Animals; D049109:Cell Proliferation; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D051959:ELAV Proteins / Q000502:physiology*; D005347:Fibroblasts / Q000502:physiology*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D007333:Insulin Resistance; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D055550:Protein Stability; D021381:Protein Transport; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism; D000097796:Nucleolin
chemical_list: D020121:5' Untranslated Regions; D019941:Cyclin-Dependent Kinase Inhibitor p16; D051959:ELAV Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C417743:Cdkn2a protein, mouse