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Loss of p16Ink4a Function Rescues Cellular Senescence Induced by Telomere Dysfunction
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
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Received: 11 February 2012; in revised form: 3 May 2012 / Accepted: 10 May 2012 / Published: 16 May 2012
Abstract: p16Ink4a is a tumor suppressor and a marker for cellular senescence. Previous studies have shown that p16Ink4a plays an important role in the response to DNA damage signals caused by telomere dysfunction. In this study, we crossed Wrn−/− and p16Ink4a−/− mice to knock out the p16Ink4a function in a Wrn null background. Growth curves showed that loss of p16Ink4a 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 p16Ink4a 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∆B∆M, loss of p16Ink4a could partially overcome the DNA damage response by disabling p16Ink4a up-regulation and reducing the accumulation of γ-H2AX that is observed in Wrn−/− MEFs. Furthermore, in response to TRF2∆B∆M overexpression, Wrn−/− MEFs senesced within several passages. In contrast, p16Ink4a−/− and p16Ink4a−/−Wrn−/− MEFs could continuously grow and lose expression of the exogenous TRF2∆B∆M in their late passages. In summary, our data suggest that in the context of telomere dysfunction, loss of p16Ink4a function could prevent cells from senescence. These results shed light on the anti-aging strategy through regulation of p16Ink4a expression.
Keywords: p16Ink4a; Werner Syndrome; telomere dysfunction
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Zhang, X.; Wu, X.; Tang, W.; Luo, Y. Loss of p16Ink4a Function Rescues Cellular Senescence Induced by Telomere Dysfunction. Int. J. Mol. Sci. 2012, 13, 5866-5877.
Zhang X, Wu X, Tang W, Luo Y. Loss of p16Ink4a Function Rescues Cellular Senescence Induced by Telomere Dysfunction. International Journal of Molecular Sciences. 2012; 13(5):5866-5877.
Zhang, Xiufeng; Wu, Xiaoming; Tang, Wenru; Luo, Ying. 2012. "Loss of p16Ink4a Function Rescues Cellular Senescence Induced by Telomere Dysfunction." Int. J. Mol. Sci. 13, no. 5: 5866-5877.