Ablation of the p16(INK4a) tumour suppressor reverses ageing phenotypes of klotho mice.
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.
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.|CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
Seidai
S
Sato
Division of Cancer Biology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.|Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba 278-8510, Japan.
Yuka
Y
Kawamata
Division of Cancer Biology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
Akiko
A
Takahashi
Division of Cancer Biology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
Yoshinori
Y
Imai
Division of Cancer Biology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
Aki
A
Hanyu
Division of Cancer Biology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
Atsushi
A
Okuma
Division of Cancer Biology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
Masaki
M
Takasugi
Division of Cancer Biology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
Kimi
K
Yamakoshi
Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
Hiroyuki
H
Sorimachi
Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
Hiroaki
H
Kanda
Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
Yuichi
Y
Ishikawa
Department of Respiratory Medicine and Rheumatology, University of Tokushima Graduate School of Medicine, Tokushima 770-8503, Japan.
Saburo
S
Sone
Department of Respiratory Medicine and Rheumatology, University of Tokushima Graduate School of Medicine, Tokushima 770-8503, Japan.
Yasuhiko
Y
Nishioka
Division of Cancer Biology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.|Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba 278-8510, Japan.|PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
Naoko
N
Ohtani
Division of Cancer Biology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.|CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.|Department of Molecular Microbiology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
Eiji
E
Hara
D000375:Aging / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D005786:Gene Expression Regulation; D019942:Genes, p16; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011401:Promoter Regions, Genetic
D019941:Cyclin-Dependent Kinase Inhibitor p16; D005966:Glucuronidase; D000090265:Klotho Proteins