Ablation of the p16(INK4a) tumour suppressor reverses ageing phenotypes of klotho mice

作者：Sato Seidai; Kawamata Yuka; Takahashi Akiko; Imai Yoshinori; Hanyu Aki; Okuma Atsushi; Takasugi Masaki; Yamakoshi Kimi; Sorimachi Hiroyuki; Kanda Hiroaki; Ishikawa Yuichi; Sone Saburo; Nishioka Yasuhiko; Ohtani Naoko^*; Hara Eiji

来源：Nature Communications, 2015, 6(1): 7035.

DOI：10.1038/ncomms8035

The p16(INK4a) tumour suppressor has an established role in the implementation of cellular senescence in stem/progenitor cells, which is thought to contribute to organismal ageing. However, since p16(INK4a) knockout mice die prematurely from cancer, whether p16(INK4a) reduces longevity remains unclear. Here we show that, in mutant mice homozygous for a hypomorphic allele of the alpha-klotho ageing-suppressor gene (kl(kl/kl)), accelerated ageing phenotypes are rescued by p16(INK4a) ablation. Surprisingly, this is due to the restoration of alpha-klotho expression in kl(kl/kl) mice and does not occur when p16(INK4a) is ablated in alpha-klotho knockout mice (kl(-/-)), suggesting that p16(INK4a) is an upstream regulator of alpha-klotho expression. Indeed, p16(INK4a) represses alpha-klotho promoter activity by blocking the functions of E2Fs. These results, together with the observation that the expression levels of p16(INK4a) are inversely correlated with those of alpha-klotho throughout ageing, indicate that p16(INK4a) plays a previously unrecognized role in downregulating alpha-klotho expression during ageing.

• 出版日期2015-4
• 单位河北医科大学