The p38-activated ER stress-ATF6a axis mediates cellular senescence

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

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)


The importance of proteostasis in preventing cellular senescencehasbeenwell recognized.However, the exactmechanism 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)6a 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, andMRC-5. NBR1 bound to p38 MAPK, preferentially to an active form, and upon NBR1 abrogation, the activity of p38 increased. NADPH oxidasewas activatedinturnby p38, and the resulting oxidative stress triggeredERstress. Itwas found thatERstress mediated cellular senescence through the UPR sensor ATF6a. Knockdown of ATF6a prevented senescence, whereas ATF6a overexpression triggered it. The transcriptional activity of ATF6a was important. The ER stress- ATF6a axis alsomediated cellular senescence induced byH-RasV12 overexpression andUVirradiation, suggesting a common role of this axis in senescence induction. In summary,we presented an evidence for the novel role of the ERstress-ATF6a axis in cellular senescence.

Original languageEnglish
Pages (from-to)2422-2434
Number of pages13
JournalFASEB Journal
Issue number2
Publication statusPublished - 2019

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) funded by the Korean Government (Grant NRF-2014R1A1A2058003 to J.S.), and the Korea University Executive Vice President for Medical Affairs (Grant K1723221 to J.S.). The authors declare no conflicts of interest.

Publisher Copyright:
© 2019 FASEB.


  • NADPH oxidase
  • NBR1
  • Oxidative stress
  • Ras
  • p53

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics


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