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The p38-activated ER stress-ATF6 axis mediates cellular senescence

Authors
Kim, Hee SukKim, YongjinLim, Min JaePark, Yun-GyuPark, Serk InSohn, Jeongwon
Issue Date
2월-2019
Publisher
FEDERATION AMER SOC EXP BIOL
Keywords
NBR1; NADPH oxidase; oxidative stress; p53; Ras
Citation
FASEB JOURNAL, v.33, no.2, pp.2422 - 2434
Indexed
SCIE
SCOPUS
Journal Title
FASEB JOURNAL
Volume
33
Number
2
Start Page
2422
End Page
2434
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/67718
DOI
10.1096/fj.201800836R
ISSN
0892-6638
Abstract
The importance of proteostasis in preventing cellular senescence has been well recognized. However, the exact mechanism by which the loss of proteostasis or endoplasmic reticulum (ER) stress induces cellular senescence remains unclear. We report that ER stress mediates cellular senescence through the activating transcription factor (ATF)6 branch of the unfolded protein response (UPR). Cellular senescence was induced by the abrogation of neighbor of breast cancer (BRCA)1 gene (NBR1). NBR1 abrogation-induced senescence was p53 dependent and observed in both transformed and nontransformed human cell lines: MCF-7, Caki-1, and MRC-5. NBR1 bound to p38 MAPK, preferentially to an active form, and upon NBR1 abrogation, the activity of p38 increased. NADPH oxidase was activated in turn by p38, and the resulting oxidative stress triggered ER stress. It was found that ER stress mediated cellular senescence through the UPR sensor ATF6. Knockdown of ATF6 prevented senescence, whereas ATF6 overexpression triggered it. The transcriptional activity of ATF6 was important. The ER stress-ATF6 axis also mediated cellular senescence induced by H-RasV12 overexpression and UV irradiation, suggesting a common role of this axis in senescence induction. In summary, we presented an evidence for the novel role of the ER stress-ATF6 axis in cellular senescence.Kim, H. S., Kim, Y., Lim, M. J., Park, Y.-G., Park, S. I., Sohn, J. The p38-activated ER stress-ATF6 axis mediates cellular senescence.
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