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The p38‐activated ER stress‐ATF6α axis mediates cellular senescence
Author(s) -
Kim Hee Suk,
Kim Yongjin,
Lim Min Jae,
Park Yun-Gyu,
Park Serk In,
Sohn Jeongwon
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201800836r
Subject(s) - senescence , atf6 , proteostasis , microbiology and biotechnology , unfolded protein response , endoplasmic reticulum , activating transcription factor , gene knockdown , biology , p38 mitogen activated protein kinases , cell culture , mapk/erk pathway , signal transduction , genetics
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)6α 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 ATF6α. Knockdown of ATF6α prevented senescence, whereas ATF6α overexpression triggered it. The transcriptional activity of ATF6α was important. The ER stress‐ATF6α 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‐ATF6α 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‐ATF6α axis mediates cellular senescence. FASEB J. 33, 2422–2434 (2019). www.fasebj.org