title: Increased stability of the p16 mRNA with replicative senescence.
abstract: Expression of p16(INK4a) is elevated during ageing and replicative senescence. Here, we report the presence of an instability determinant within the 3'-untranslated region (UTR) of the p16 messenger RNA in WI-38 human diploid fibroblasts. The p16 3'UTR was found to be a specific target of AUF1, an RNA-binding protein implicated in promoting mRNA decay. Both AUF1 levels and AUF1-p16 mRNA associations were strikingly more abundant in early-passage than late-passage fibroblast cultures. Moreover, short interfering RNA-based reductions in AUF1 levels increased the stability of p16 3'UTR-containing transcripts, elevated the expression of p16 and accentuated the senescence phenotype. Together, our findings show that p16 mRNA turnover decreases during replicative senescence and that the instability-conferring region is located within the 3'UTR of p16, as well as identifying AUF1 as a critical mediator of these regulatory events.
authors.affiliation: Laboratory of Cellular and Molecular Biology, National Institute on Aging-IRP, NIH, Baltimore, Maryland 21224, USA.
authors.forename: Wengong
authors.initials: W
authors.lastname: Wang
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Martindale
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Yang
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Chrest
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
mesh_terms: D020413:3' Untranslated Regions; D001483:Base Sequence; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D012333:RNA, Messenger
chemical_list: D020413:3' Untranslated Regions; D019941:Cyclin-Dependent Kinase Inhibitor p16; C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; D012333:RNA, Messenger