Cellular senescence is the state of irreversible cell cycle arrest provoked by a variety of potentially oncogenic stimuli, such as telomere shortening, DNA damage or activation of certain oncogenes. Cellular senescence appears to be acting as a barrier to cancer, preventing damaged cells from undergoing aberrant proliferation. On the other hand, it has been proven that senescent cells are accumulating during aging process throughout living body and secrete many inflammatory proteins into the surrounding extracellular fluid. This phenomenon is called senescence-associated secretory phenotype (SASP), suggesting that SASP factors promote some age-associated diseases such as chronic inflammation and cancer. We have tried to reveal the molecular mechanisms why SASP factor gene expressions are upregulated in senescent cells. In our laboratory, we are aiming to understand the molecular mechanisms of cellular senescence and SASP. Our research will provide valuable new insights into the development of age-associated pathology including cancer and provide us new possibilities of its control.
- Wakita, M., Takahashi, A., Sano, O., Loo, T.M., Imai, Y., Narukawa, M., Iwata, H., Matsudaira, T., Kawamoto, K., Ohtani, N., Yoshimori, T. and Hara, E.
- A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells. Nature Communications, 11, 1935 doi: 10.1038/s41467-020-15719-6 (2020).
- Loo, T.M., Miyata, K., Tanaka, Y., & Takahashi, A.
Cellular senescence and senescence‐associated secretory phenotype via the cGAS‐STING signaling pathway in cancer
Cancer Science, 111, 304-311 (2020)
- Takahashi, A., Loo, T.M., Okada, R., Kamachi, F., Watanabe, Y., Wakita, M., Watanabe, S., Kawamoto, S., Miyata, K., Barber, G.N., Ohtani, N. and Hara, E.
- Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells.
Nature Communications, 9, 1249 doi:10.1038/s41467-018-03555-8 (2018).
- Takasugi, M., Okada, R., Takahashi, A., Chen, D., Watanabe, S., Hara, E.
Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2.
Nature Communications, 8, 15729 doi:10.1038/ncomms15728 (2017).
- *Takahashi, A., Okada, R., Nagao, K., Kawamata, Y., Hanyu, A., Yoshimoto, S., Takasugi, M., Watanabe, S., Kanemaki, M., Obuse, C. and *Hara, E.
- Exosomes maintain cellular homeostasis by excreting harmful DNA from cells.
Nature Communications, 8, 15287 (2017)
(*Takahashi and Hara are co-corresponding to this paper.)
- *Sato, S., *Kawamata, Y., *Takahashi, A., *Imai, Y., Hanyu, A., Okuma, A., Takasugi, M., Yamakoshi, K, Sorimachi, H., Sone, S., Nishioka, Y, Ohtani, N. and Hara, E.
- Ablation of the p16INK4a tumour suppressor reverses ageing phenotypes of klotho mice.
Nature Communications, 6: 7035 doi: 10.1038/ncomms8035 (2015).
(*Sato, Kawamata, Takahashi and Imai contributed equally to this paper.)
- Imai, Y., Takahashi, A., Hanyu, A., Hori, S., Sato, S., Naka, K., Hirao, A., Ohtani, N. and Hara, E.
- Crosstalk between the Rb Pathway and AKT Signaling Forms a Quiescence-Senescence Switch.
Cell Rep., 7, 194-207 (2014)
- Takahashi, A., Imai, Y., Yamakoshi, K., Kuninaka, S., Ohtani, N., Yoshimoto, S., Hori, S., Tachibana, M., Anderton, E., Takeuchi, T., Shinkai, Y., Peters, G., Saya, H. & Hara, E..
- DNA Damage Signaling Triggers Degradation of Histone Methyltransferases through APC/C(Cdh1) in Senescent Cells.
Mol Cell. 45, 123-131 (2012)
- Takeuchi, S., Takahashi, A., Motoi, N., Tajima, T., Yamakoshi, K., Yoshimoto, S., Hirao, A., Yanagi, S., Fukami, K., Ishikawa, Y., Sone, S. & Hara, E..
- Intrinsic cooperation between p16INK4a and p21Waf1/Cip1 in the onset of cellular senescence and tumor suppression in vivo.
Cancer Res. 70, 9381-9390 (2010)
- *Yamakoshi, K., *Takahashi, A., Hirose, F., Nakayama, R., Ishimaru, N., Kubo, Y., Mann, D.J., Ohmura, M., Hirao, A., Saya, H., Arase, S., Hayashi, Y., Nakao, K., Matsumoto, M., Ohtani, N. & Hara, E..
- Real-time in vivo imaging of p16Ink4a reveals crosstalk with p53
J. Cell Biol., 186, 393-407 (2009)
(*Yamakoshi and Takahashi contributed equally to this paper.)
- Takahashi, A., Ohtani, N., Yamakoshi, K., Iida, S., Tahara, H.,Nakayama, K., Nakayama, K.I., Ide, T., Saya, H. & Hara, E..
- Mitogenic signalling and the p16INK4a/Rb pathway co-operate to enforce irreversible cellular senescence
Nature Cell Biol., 8, 1291-1297 (2006)
Project for Cellular senescence (Project leader)
The Cancer Institute for Japanese Foundation for Cancer Research
3-8-31, Ariake, Koto-ku, Tokyo 135-8550 Japan
Phone： +81-3-3520-0111 (Ext. 5351)