The p38-activated ER stress-ATF6α axis mediates cellular senescence

Hee Suk Kim, Yongjin Kim, Min Jae Lim, Yun Gyu Park, Serkin Park, Jeongwon Sohn

Research output: Contribution to journalArticle

1 Citation (Scopus)

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)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.

Original languageEnglish
Pages (from-to)2422-2434
Number of pages13
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume33
Issue number2
DOIs
Publication statusPublished - 2019 Feb 1

Fingerprint

Endoplasmic Reticulum Stress
Cell Aging
Unfolded Protein Response
Activating Transcription Factor 6
Oxidative stress
NADPH Oxidase
p38 Mitogen-Activated Protein Kinases
Neoplasm Genes
Proteins
Genes
Cells
Irradiation
Oxidative Stress
Breast Neoplasms
Cell Line
Sensors

Keywords

  • NADPH oxidase
  • NBR1
  • oxidative stress
  • p53
  • Ras

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

The p38-activated ER stress-ATF6α axis mediates cellular senescence. / Kim, Hee Suk; Kim, Yongjin; Lim, Min Jae; Park, Yun Gyu; Park, Serkin; Sohn, Jeongwon.

In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Vol. 33, No. 2, 01.02.2019, p. 2422-2434.

Research output: Contribution to journalArticle

@article{55b2db0eeee34a0681f358f9dd44e815,
title = "The p38-activated ER stress-ATF6α axis mediates cellular senescence",
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)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.",
keywords = "NADPH oxidase, NBR1, oxidative stress, p53, Ras",
author = "Kim, {Hee Suk} and Yongjin Kim and Lim, {Min Jae} and Park, {Yun Gyu} and Serkin Park and Jeongwon Sohn",
year = "2019",
month = "2",
day = "1",
doi = "10.1096/fj.201800836R",
language = "English",
volume = "33",
pages = "2422--2434",
journal = "The FASEB journal : official publication of the Federation of American Societies for Experimental Biology",
issn = "1530-6860",
publisher = "FASEB",
number = "2",

}

TY - JOUR

T1 - The p38-activated ER stress-ATF6α axis mediates cellular senescence

AU - Kim, Hee Suk

AU - Kim, Yongjin

AU - Lim, Min Jae

AU - Park, Yun Gyu

AU - Park, Serkin

AU - Sohn, Jeongwon

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

KW - NADPH oxidase

KW - NBR1

KW - oxidative stress

KW - p53

KW - Ras

UR - http://www.scopus.com/inward/record.url?scp=85061038687&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061038687&partnerID=8YFLogxK

U2 - 10.1096/fj.201800836R

DO - 10.1096/fj.201800836R

M3 - Article

C2 - 30260700

AN - SCOPUS:85061038687

VL - 33

SP - 2422

EP - 2434

JO - The FASEB journal : official publication of the Federation of American Societies for Experimental Biology

JF - The FASEB journal : official publication of the Federation of American Societies for Experimental Biology

SN - 1530-6860

IS - 2

ER -