title: Loss of p16(Ink4a) function rescues cellular senescence induced by telomere dysfunction.
abstract: p16(Ink4a) is a tumor suppressor and a marker for cellular senescence. Previous studies have shown that p16(Ink4a) plays an important role in the response to DNA damage signals caused by telomere dysfunction. In this study, we crossed Wrn(-/-) and p16(Ink4a-/-) mice to knock out the p16(Ink4a) function in a Wrn null background. Growth curves showed that loss of p16(Ink4a) could rescue the growth barriers that are observed in Wrn(-/-) mouse embryonic fibroblasts (MEFs). By challenging the MEFs with the global genotoxin doxorubicin, we showed that loss of p16(Ink4a) did not dramatically affect the global DNA damage response of Wrn(-/-) MEFs induced by doxorubicin. However, in response to telomere dysfunction initiated by the telomere damaging protein TRF2(ΔBΔM), loss of p16(Ink4a) could partially overcome the DNA damage response by disabling p16(Ink4a) up-regulation and reducing the accumulation of γ-H2AX that is observed in Wrn(-/-) MEFs. Furthermore, in response to TRF2(ΔBΔM) overexpression, Wrn(-/-) MEFs senesced within several passages. In contrast, p16(Ink4a-/-) and p16(Ink4a-/-)Wrn(-/-) MEFs could continuously grow and lose expression of the exogenous TRF2(ΔBΔM) in their late passages. In summary, our data suggest that in the context of telomere dysfunction, loss of p16(Ink4a) function could prevent cells from senescence. These results shed light on the anti-aging strategy through regulation of p16(Ink4a) expression.
authors: Faculty of Environmental Science and Engineering, Kunming University of Science & Technology, Kunming 650224, China.|Lab of Molecular Genetics of Aging & Tumor, Faculty of Life Science and Technology, Kunming University of Science & Technology, Kunming 650224, China.
authors: Xiufeng
authors: X
authors: Zhang
authors: Faculty of Environmental Science and Engineering, Kunming University of Science & Technology, Kunming 650224, China.|Lab of Molecular Genetics of Aging & Tumor, Faculty of Life Science and Technology, Kunming University of Science & Technology, Kunming 650224, China.
authors: Xiaoming
authors: X
authors: Wu
authors: Faculty of Environmental Science and Engineering, Kunming University of Science & Technology, Kunming 650224, China.|Lab of Molecular Genetics of Aging & Tumor, Faculty of Life Science and Technology, Kunming University of Science & Technology, Kunming 650224, China.
authors: Wenru
authors: W
authors: Tang
authors: Faculty of Environmental Science and Engineering, Kunming University of Science & Technology, Kunming 650224, China.|Lab of Molecular Genetics of Aging & Tumor, Faculty of Life Science and Technology, Kunming University of Science & Technology, Kunming 650224, China.
authors: Ying
authors: Y
authors: Luo
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics*; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology*; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental; D055879:Gene Knock-In Techniques; D051379:Mice; D053484:RecQ Helicases / Q000172:deficiency* / Q000235:genetics; D016615:Telomere / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000071657:Werner Syndrome Helicase
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C534796:TRF2 protein, mouse; D035341:Telomeric Repeat Binding Protein 2; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D053484:RecQ Helicases; D000071657:Werner Syndrome Helicase; C499253:Wrn protein, mouse