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p16（INK4a）肿瘤抑制因子的缺失可逆转klotho小鼠的衰老表型。

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

作者信息

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

机构信息

Division of Cancer Biology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.

Department of Respiratory Medicine and Rheumatology, University of Tokushima Graduate School of Medicine, Tokushima 770-8503, Japan.

出版信息

Nat Commun. 2015 Apr 29;6:7035. doi: 10.1038/ncomms8035.

DOI:10.1038/ncomms8035
PMID:25923845
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4421814/
Abstract

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 α-klotho ageing-suppressor gene (kl(kl/kl)), accelerated ageing phenotypes are rescued by p16(INK4a) ablation. Surprisingly, this is due to the restoration of α-klotho expression in kl(kl/kl) mice and does not occur when p16(INK4a) is ablated in α-klotho knockout mice (kl(-/-)), suggesting that p16(INK4a) is an upstream regulator of α-klotho expression. Indeed, p16(INK4a) represses α-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 α-klotho throughout ageing, indicate that p16(INK4a) plays a previously unrecognized role in downregulating α-klotho expression during ageing.

摘要

p16(INK4a)肿瘤抑制因子在干细胞/祖细胞中细胞衰老的进程中发挥着既定作用，而细胞衰老被认为与机体衰老有关。然而，由于p16(INK4a)基因敲除小鼠会因癌症而过早死亡，所以p16(INK4a)是否会缩短寿命仍不清楚。在此我们表明，在α-klotho衰老抑制基因（kl(kl/kl)）的低表达等位基因纯合的突变小鼠中，p16(INK4a)基因缺失可挽救加速衰老的表型。令人惊讶的是，这是由于kl(kl/kl)小鼠中α-klotho表达的恢复，而在α-klotho基因敲除小鼠（kl(-/-)）中敲除p16(INK4a)时则不会出现这种情况，这表明p16(INK4a)是α-klotho表达的上游调节因子。事实上，p16(INK4a)通过阻断E2F的功能来抑制α-klotho启动子活性。这些结果，连同在整个衰老过程中p16(INK4a)的表达水平与α-klotho的表达水平呈负相关的观察结果，表明p16(INK4a)在衰老过程中下调α-klotho表达方面发挥了先前未被认识到的作用。

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