The p38‐activated ER stress‐ATF6α axis mediates cellular senescence
| Autor: | Min Jae Lim, Serk In Park, Hee Suk Kim, Yun Gyu Park, Jeongwon Sohn, Yongjin Kim |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Senescence p38 mitogen-activated protein kinases Activating transcription factor medicine.disease_cause p38 Mitogen-Activated Protein Kinases Biochemistry 03 medical and health sciences 0302 clinical medicine Genetics medicine Humans Molecular Biology Cellular Senescence NADPH oxidase biology Chemistry Endoplasmic reticulum Intracellular Signaling Peptides and Proteins Proteins Endoplasmic Reticulum Stress Activating Transcription Factor 6 Cell biology 030104 developmental biology Proteostasis NADPH Oxidase 4 NADPH Oxidase 2 MCF-7 Cells biology.protein Unfolded protein response Tumor Suppressor Protein p53 030217 neurology & neurosurgery Oxidative stress Biotechnology |
| Zdroj: | The FASEB Journal. 33:2422-2434 |
| ISSN: | 1530-6860 0892-6638 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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