Loss of p16(Ink4a) function rescues cellular senescence induced by telomere dysfunction.
Loss of p16(Ink4a) function rescues cellular senescence induced by telomere dysfunction.
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DOI：
10.3390/ijms13055866
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发表时间：
2012
影响因子：
5.6
通讯作者：
Luo Y
中科院分区：
文献类型：
--
作者：
Zhang X;Wu X;Tang W;Luo Y
p16 Ink 4a是肿瘤抑制因子和细胞衰老的标志物。已有研究表明p16 Ink 4a在端粒功能障碍引起的DNA损伤信号应答中起重要作用。在这项研究中，我们将p16 Ink 4a −/−和p16 Ink 4a −/−小鼠杂交，以在p16 Ink 4a无效背景下敲除p16 Ink 4a功能。生长曲线显示，p16 Ink 4a的缺失可以挽救在哺乳动物胚胎成纤维细胞（MEFs）中观察到的生长障碍。通过用全局遗传毒素阿霉素挑战MEFs，我们发现p16 Ink 4a的缺失并没有显著影响阿霉素诱导的BRN-/-MEFs的全局DNA损伤反应。然而，在对端粒损伤蛋白TRF 2 ΔBΔM引发的端粒功能障碍的反应中，p16 Ink 4a的缺失可以通过使p16 Ink 4a上调失效并减少在p16-/-MEFs中观察到的γ-H2 AX的积累来部分克服DNA损伤反应。此外，响应于TRF 2 ΔBΔM的过表达，在几代内，TRF-/-MEFs衰老。相比之下，p16 Ink 4a −/−和p16 Ink 4a −/− Ink 4 n −/− MEFs可以持续生长，并在其晚期传代中失去外源性TRF 2 ΔBΔM的表达。总之，我们的数据表明，在端粒功能障碍的情况下，p16 Ink 4a功能的丧失可以防止细胞衰老。这些结果揭示了通过调节p16 Ink 4a表达的抗衰老策略。
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 TRF2ΔBΔM, 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 TRF2ΔBΔM overexpression, Wrn−/− MEFs senesced within several passages. In contrast, p16Ink4a−/− and p16Ink4a−/−Wrn−/− MEFs could continuously grow and lose expression of the exogenous TRF2ΔBΔM 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.
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DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
DOI：
10.3724/sp.j.1005.2009.00451
发表时间：
2009-05-01
期刊：
Yichuan
影响因子：
--
作者：
Zhang Xiu-Feng;Tang Wen-Ru;Luo Ying
通讯作者：
Luo Ying
影响因子：
56.9
作者：
Crabbe, L;Verdun, RE;Karlseder, J
通讯作者：
Karlseder, J
影响因子：
3.7
作者：
Minty, Fay;Thurlow, Johanna K.;Parkinson, E. Kenneth
通讯作者：
Parkinson, E. Kenneth
影响因子：
8
作者：
Palmero, I;McConnell, B;Peters, G
通讯作者：
Peters, G