FBXW7 Confers Radiation Survival by Targeting p53 for Degradation
Summary: The tumor suppressor p53 plays a critical role in integrating a wide variety of stress responses. Therefore, p53 levels are precisely regulated by multiple ubiquitin ligases. In this study, we report that FBXW7, a substrate recognition component of the SKP1-CUL1-F-box (SCF) E3 ligase, inter...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-01-01
|
| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719316821 |
| _version_ | 1828894612613234688 |
|---|---|
| author | Danrui Cui Xiufang Xiong Jianfeng Shu Xiaoqing Dai Yi Sun Yongchao Zhao |
| author_facet | Danrui Cui Xiufang Xiong Jianfeng Shu Xiaoqing Dai Yi Sun Yongchao Zhao |
| author_sort | Danrui Cui |
| collection | DOAJ |
| description | Summary: The tumor suppressor p53 plays a critical role in integrating a wide variety of stress responses. Therefore, p53 levels are precisely regulated by multiple ubiquitin ligases. In this study, we report that FBXW7, a substrate recognition component of the SKP1-CUL1-F-box (SCF) E3 ligase, interacts with and targets p53 for polyubiquitination and proteasomal degradation after exposure to ionizing radiation or etoposide. Mechanistically, DNA damage activates ATM to phosphorylate p53 on Ser33 and Ser37, which facilitates the FBXW7 binding and subsequent p53 degradation by SCFFBXW7. Inactivation of ATM or SCFFBXW7 by small molecular inhibitors or genetic knockdown/knockout approaches extends the p53 protein half-life upon DNA damage in an MDM2-independent manner. Biologically, FBXW7 inactivation sensitizes cancer cells to radiation or etoposide by stabilizing p53 to induce cell-cycle arrest and apoptosis. Taken together, our study elucidates a mechanism by which FBXW7 confers cancer cell survival during radiotherapy or chemotherapy via p53 targeting. : In this study, Cui et al. demonstrate that upon DNA damage, ATM is activated to phosphorylate p53 to facilitate its binding with FBXW7, leading to p53 ubiquitination and proteasomal degradation. Biologically, FBXW7 inactivation sensitizes cancer cells to radiation or etoposide by stabilizing p53 to induce cell-cycle arrest and apoptosis. Keywords: FBXW7, p53, E3 ligase, DNA damage, radiosensitivity, ATM, SCF, CRL, ubiquitination, degradation |
| first_indexed | 2024-12-13T14:13:42Z |
| format | Article |
| id | doaj.art-065c84736395404caebc8dd0afd09e42 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-13T14:13:42Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-065c84736395404caebc8dd0afd09e422022-12-21T23:42:22ZengElsevierCell Reports2211-12472020-01-01302497509.e4FBXW7 Confers Radiation Survival by Targeting p53 for DegradationDanrui Cui0Xiufang Xiong1Jianfeng Shu2Xiaoqing Dai3Yi Sun4Yongchao Zhao5Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, ChinaInstitute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China; Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaKey Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, ChinaKey Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, ChinaInstitute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China; Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USAKey Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China; Corresponding authorSummary: The tumor suppressor p53 plays a critical role in integrating a wide variety of stress responses. Therefore, p53 levels are precisely regulated by multiple ubiquitin ligases. In this study, we report that FBXW7, a substrate recognition component of the SKP1-CUL1-F-box (SCF) E3 ligase, interacts with and targets p53 for polyubiquitination and proteasomal degradation after exposure to ionizing radiation or etoposide. Mechanistically, DNA damage activates ATM to phosphorylate p53 on Ser33 and Ser37, which facilitates the FBXW7 binding and subsequent p53 degradation by SCFFBXW7. Inactivation of ATM or SCFFBXW7 by small molecular inhibitors or genetic knockdown/knockout approaches extends the p53 protein half-life upon DNA damage in an MDM2-independent manner. Biologically, FBXW7 inactivation sensitizes cancer cells to radiation or etoposide by stabilizing p53 to induce cell-cycle arrest and apoptosis. Taken together, our study elucidates a mechanism by which FBXW7 confers cancer cell survival during radiotherapy or chemotherapy via p53 targeting. : In this study, Cui et al. demonstrate that upon DNA damage, ATM is activated to phosphorylate p53 to facilitate its binding with FBXW7, leading to p53 ubiquitination and proteasomal degradation. Biologically, FBXW7 inactivation sensitizes cancer cells to radiation or etoposide by stabilizing p53 to induce cell-cycle arrest and apoptosis. Keywords: FBXW7, p53, E3 ligase, DNA damage, radiosensitivity, ATM, SCF, CRL, ubiquitination, degradationhttp://www.sciencedirect.com/science/article/pii/S2211124719316821 |
| spellingShingle | Danrui Cui Xiufang Xiong Jianfeng Shu Xiaoqing Dai Yi Sun Yongchao Zhao FBXW7 Confers Radiation Survival by Targeting p53 for Degradation Cell Reports |
| title | FBXW7 Confers Radiation Survival by Targeting p53 for Degradation |
| title_full | FBXW7 Confers Radiation Survival by Targeting p53 for Degradation |
| title_fullStr | FBXW7 Confers Radiation Survival by Targeting p53 for Degradation |
| title_full_unstemmed | FBXW7 Confers Radiation Survival by Targeting p53 for Degradation |
| title_short | FBXW7 Confers Radiation Survival by Targeting p53 for Degradation |
| title_sort | fbxw7 confers radiation survival by targeting p53 for degradation |
| url | http://www.sciencedirect.com/science/article/pii/S2211124719316821 |
| work_keys_str_mv | AT danruicui fbxw7confersradiationsurvivalbytargetingp53fordegradation AT xiufangxiong fbxw7confersradiationsurvivalbytargetingp53fordegradation AT jianfengshu fbxw7confersradiationsurvivalbytargetingp53fordegradation AT xiaoqingdai fbxw7confersradiationsurvivalbytargetingp53fordegradation AT yisun fbxw7confersradiationsurvivalbytargetingp53fordegradation AT yongchaozhao fbxw7confersradiationsurvivalbytargetingp53fordegradation |