Ablation of the p16INK4a tumour suppressor reverses ageing phenotypes of klotho mice

Seidai Sato, Yuka Kawamata, Akiko Takahashi, Yoshinori Imai, Aki Hanyu, Atsushi Okuma, Masaki Takasugi, Kimi Yamakoshi, Hiroyuki Sorimachi, Hiroaki Kanda, Yuichi Ishikawa, Saburo Sone, Yasuhiko Nishioka, Naoko Ohtani () and Eiji Hara ()
Additional contact information
Seidai Sato: Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku
Yuka Kawamata: Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku
Akiko Takahashi: Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku
Yoshinori Imai: Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku
Aki Hanyu: Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku
Atsushi Okuma: Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku
Masaki Takasugi: Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku
Kimi Yamakoshi: Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku
Hiroyuki Sorimachi: Tokyo Metropolitan Institute of Medical Science
Hiroaki Kanda: Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku
Yuichi Ishikawa: Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku
Saburo Sone: University of Tokushima Graduate School of Medicine
Yasuhiko Nishioka: University of Tokushima Graduate School of Medicine
Naoko Ohtani: Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku
Eiji Hara: Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: Abstract The p16INK4a 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 p16INK4a knockout mice die prematurely from cancer, whether p16INK4a reduces longevity remains unclear. Here we show that, in mutant mice homozygous for a hypomorphic allele of the α-klotho ageing-suppressor gene (klkl/kl), accelerated ageing phenotypes are rescued by p16INK4a ablation. Surprisingly, this is due to the restoration of α-klotho expression in klkl/kl mice and does not occur when p16INK4a is ablated in α-klotho knockout mice (kl−/−), suggesting that p16INK4a is an upstream regulator of α-klotho expression. Indeed, p16INK4a represses α-klotho promoter activity by blocking the functions of E2Fs. These results, together with the observation that the expression levels of p16INK4a are inversely correlated with those of α-klotho throughout ageing, indicate that p16INK4a plays a previously unrecognized role in downregulating α-klotho expression during ageing.

Date: 2015
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms8035 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8035

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms8035

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().