p53N236S Activates Autophagy in Response to Hypoxic Stress Induced by DFO
Hypoxia can lead to stabilization of the tumor suppressor gene p53 and cell death. However, p53 mutations could promote cell survival in a hypoxic environment. In this study, we found that p53N236S (p53N239S in humans, hereinafter referred to as p53S) mutant mouse embryonic fibroblasts (MEFs) resist...
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MDPI AG
2022-04-01
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| Online Access: | https://www.mdpi.com/2073-4425/13/5/763 |
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| author | Kang Gao Huanhuan Zong Kailong Hou Yanduo Zhang Ruyi Zhang Dan Zhao Xin Guo Ying Luo Shuting Jia |
| author_facet | Kang Gao Huanhuan Zong Kailong Hou Yanduo Zhang Ruyi Zhang Dan Zhao Xin Guo Ying Luo Shuting Jia |
| author_sort | Kang Gao |
| collection | DOAJ |
| description | Hypoxia can lead to stabilization of the tumor suppressor gene p53 and cell death. However, p53 mutations could promote cell survival in a hypoxic environment. In this study, we found that p53N236S (p53N239S in humans, hereinafter referred to as p53S) mutant mouse embryonic fibroblasts (MEFs) resistant to deferoxamine (DFO) mimic a hypoxic environment. Further, Western blot and flow cytometry showed reduced apoptosis in <i>p53<sup>S/S</sup></i> cells compared to WT after DFO treatment, suggesting an antiapoptosis function of p53S mutation in response to hypoxia-mimetic DFO. Instead, <i>p53<sup>S/S</sup></i> cells underwent autophagy in response to hypoxia stress presumably through inhibition of the AKT/mTOR pathway, and this process was coupled with nuclear translocation of p53S protein. To understand the relationship between autophagy and apoptosis in <i>p53<sup>S/S</sup></i> cells in response to hypoxia, the autophagic inhibitor 3-MA was used to treat both WT and <i>p53<sup>S/S</sup></i> cells after DFO exposure. Both apoptotic signaling and cell death were enhanced by autophagy inhibition in <i>p53<sup>S/S</sup></i> cells. In addition, the mitochondrial membrane potential (MMP) and the ROS level results indicated that p53S might initiate mitophagy to clear up damaged mitochondria in response to hypoxic stress, thus increasing the proportion of intact mitochondria and maintaining cell survival. In conclusion, the p53S mutant activates autophagy instead of inducing an apoptotic process in response to hypoxia stress to protect cells from death. |
| first_indexed | 2024-03-10T03:49:55Z |
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| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T03:49:55Z |
| publishDate | 2022-04-01 |
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| series | Genes |
| spelling | doaj.art-0ad084fa67e24c22961254aa23399f4c2023-11-23T11:09:03ZengMDPI AGGenes2073-44252022-04-0113576310.3390/genes13050763p53N236S Activates Autophagy in Response to Hypoxic Stress Induced by DFOKang Gao0Huanhuan Zong1Kailong Hou2Yanduo Zhang3Ruyi Zhang4Dan Zhao5Xin Guo6Ying Luo7Shuting Jia8Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, ChinaLaboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, ChinaLaboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, ChinaLaboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, ChinaLaboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, ChinaLaboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, ChinaLaboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, ChinaGuizhou Provincial Key Laboratory of Pathogenesis and Drug Development on Common Chronic Diseases, School of Basic Medicine, Guizhou Medical University, Guiyang 550000, ChinaLaboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, ChinaHypoxia can lead to stabilization of the tumor suppressor gene p53 and cell death. However, p53 mutations could promote cell survival in a hypoxic environment. In this study, we found that p53N236S (p53N239S in humans, hereinafter referred to as p53S) mutant mouse embryonic fibroblasts (MEFs) resistant to deferoxamine (DFO) mimic a hypoxic environment. Further, Western blot and flow cytometry showed reduced apoptosis in <i>p53<sup>S/S</sup></i> cells compared to WT after DFO treatment, suggesting an antiapoptosis function of p53S mutation in response to hypoxia-mimetic DFO. Instead, <i>p53<sup>S/S</sup></i> cells underwent autophagy in response to hypoxia stress presumably through inhibition of the AKT/mTOR pathway, and this process was coupled with nuclear translocation of p53S protein. To understand the relationship between autophagy and apoptosis in <i>p53<sup>S/S</sup></i> cells in response to hypoxia, the autophagic inhibitor 3-MA was used to treat both WT and <i>p53<sup>S/S</sup></i> cells after DFO exposure. Both apoptotic signaling and cell death were enhanced by autophagy inhibition in <i>p53<sup>S/S</sup></i> cells. In addition, the mitochondrial membrane potential (MMP) and the ROS level results indicated that p53S might initiate mitophagy to clear up damaged mitochondria in response to hypoxic stress, thus increasing the proportion of intact mitochondria and maintaining cell survival. In conclusion, the p53S mutant activates autophagy instead of inducing an apoptotic process in response to hypoxia stress to protect cells from death.https://www.mdpi.com/2073-4425/13/5/763p53N236Sautophagydeferoxamine |
| spellingShingle | Kang Gao Huanhuan Zong Kailong Hou Yanduo Zhang Ruyi Zhang Dan Zhao Xin Guo Ying Luo Shuting Jia p53N236S Activates Autophagy in Response to Hypoxic Stress Induced by DFO Genes p53N236S autophagy deferoxamine |
| title | p53N236S Activates Autophagy in Response to Hypoxic Stress Induced by DFO |
| title_full | p53N236S Activates Autophagy in Response to Hypoxic Stress Induced by DFO |
| title_fullStr | p53N236S Activates Autophagy in Response to Hypoxic Stress Induced by DFO |
| title_full_unstemmed | p53N236S Activates Autophagy in Response to Hypoxic Stress Induced by DFO |
| title_short | p53N236S Activates Autophagy in Response to Hypoxic Stress Induced by DFO |
| title_sort | p53n236s activates autophagy in response to hypoxic stress induced by dfo |
| topic | p53N236S autophagy deferoxamine |
| url | https://www.mdpi.com/2073-4425/13/5/763 |
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