Cyclin B1/Cdk1 phosphorylation of mitochondrial p53 induces anti-apoptotic response.
The pro-apoptotic function of p53 has been well defined in preventing genomic instability and cell transformation. However, the intriguing fact that p53 contributes to a pro-survival advantage of tumor cells under DNA damage conditions raises a critical question in radiation therapy for the 50% huma...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2010-08-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2925892?pdf=render |
| _version_ | 1811193601539964928 |
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| author | Danupon Nantajit Ming Fan Nadire Duru Yunfei Wen John C Reed Jian Jian Li |
| author_facet | Danupon Nantajit Ming Fan Nadire Duru Yunfei Wen John C Reed Jian Jian Li |
| author_sort | Danupon Nantajit |
| collection | DOAJ |
| description | The pro-apoptotic function of p53 has been well defined in preventing genomic instability and cell transformation. However, the intriguing fact that p53 contributes to a pro-survival advantage of tumor cells under DNA damage conditions raises a critical question in radiation therapy for the 50% human cancers with intact p53 function. Herein, we reveal an anti-apoptotic role of mitochondrial p53 regulated by the cell cycle complex cyclin B1/Cdk1 in irradiated human colon cancer HCT116 cells with p53(+/+) status. Steady-state levels of p53 and cyclin B1/Cdk1 were identified in the mitochondria of many human and mouse cells, and their mitochondrial influx was significantly enhanced by radiation. The mitochondrial kinase activity of cyclin B1/Cdk1 was found to specifically phosphorylate p53 at Ser-315 residue, leading to enhanced mitochondrial ATP production and reduced mitochondrial apoptosis. The improved mitochondrial function can be blocked by transfection of mutant p53 Ser-315-Ala, or by siRNA knockdown of cyclin B1 and Cdk1 genes. Enforced translocation of cyclin B1 and Cdk1 into mitochondria with a mitochondrial-targeting-peptide increased levels of Ser-315 phosphorylation on mitochondrial p53, improved ATP production and decreased apoptosis by sequestering p53 from binding to Bcl-2 and Bcl-xL. Furthermore, reconstitution of wild-type p53 in p53-deficient HCT116 p53(-/-) cells resulted in an increased mitochondrial ATP production and suppression of apoptosis. Such phenomena were absent in the p53-deficient HCT116 p53(-/-) cells reconstituted with the mutant p53. These results demonstrate a unique anti-apoptotic function of mitochondrial p53 regulated by cyclin B1/Cdk1-mediated Ser-315 phosphorylation in p53-wild-type tumor cells, which may provide insights for improving the efficacy of anti-cancer therapy, especially for tumors that retain p53. |
| first_indexed | 2024-04-12T00:12:00Z |
| format | Article |
| id | doaj.art-dd324a10315d480bb79679d1fe6982ec |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T00:12:00Z |
| publishDate | 2010-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-dd324a10315d480bb79679d1fe6982ec2022-12-22T03:55:56ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-08-0158e1234110.1371/journal.pone.0012341Cyclin B1/Cdk1 phosphorylation of mitochondrial p53 induces anti-apoptotic response.Danupon NantajitMing FanNadire DuruYunfei WenJohn C ReedJian Jian LiThe pro-apoptotic function of p53 has been well defined in preventing genomic instability and cell transformation. However, the intriguing fact that p53 contributes to a pro-survival advantage of tumor cells under DNA damage conditions raises a critical question in radiation therapy for the 50% human cancers with intact p53 function. Herein, we reveal an anti-apoptotic role of mitochondrial p53 regulated by the cell cycle complex cyclin B1/Cdk1 in irradiated human colon cancer HCT116 cells with p53(+/+) status. Steady-state levels of p53 and cyclin B1/Cdk1 were identified in the mitochondria of many human and mouse cells, and their mitochondrial influx was significantly enhanced by radiation. The mitochondrial kinase activity of cyclin B1/Cdk1 was found to specifically phosphorylate p53 at Ser-315 residue, leading to enhanced mitochondrial ATP production and reduced mitochondrial apoptosis. The improved mitochondrial function can be blocked by transfection of mutant p53 Ser-315-Ala, or by siRNA knockdown of cyclin B1 and Cdk1 genes. Enforced translocation of cyclin B1 and Cdk1 into mitochondria with a mitochondrial-targeting-peptide increased levels of Ser-315 phosphorylation on mitochondrial p53, improved ATP production and decreased apoptosis by sequestering p53 from binding to Bcl-2 and Bcl-xL. Furthermore, reconstitution of wild-type p53 in p53-deficient HCT116 p53(-/-) cells resulted in an increased mitochondrial ATP production and suppression of apoptosis. Such phenomena were absent in the p53-deficient HCT116 p53(-/-) cells reconstituted with the mutant p53. These results demonstrate a unique anti-apoptotic function of mitochondrial p53 regulated by cyclin B1/Cdk1-mediated Ser-315 phosphorylation in p53-wild-type tumor cells, which may provide insights for improving the efficacy of anti-cancer therapy, especially for tumors that retain p53.http://europepmc.org/articles/PMC2925892?pdf=render |
| spellingShingle | Danupon Nantajit Ming Fan Nadire Duru Yunfei Wen John C Reed Jian Jian Li Cyclin B1/Cdk1 phosphorylation of mitochondrial p53 induces anti-apoptotic response. PLoS ONE |
| title | Cyclin B1/Cdk1 phosphorylation of mitochondrial p53 induces anti-apoptotic response. |
| title_full | Cyclin B1/Cdk1 phosphorylation of mitochondrial p53 induces anti-apoptotic response. |
| title_fullStr | Cyclin B1/Cdk1 phosphorylation of mitochondrial p53 induces anti-apoptotic response. |
| title_full_unstemmed | Cyclin B1/Cdk1 phosphorylation of mitochondrial p53 induces anti-apoptotic response. |
| title_short | Cyclin B1/Cdk1 phosphorylation of mitochondrial p53 induces anti-apoptotic response. |
| title_sort | cyclin b1 cdk1 phosphorylation of mitochondrial p53 induces anti apoptotic response |
| url | http://europepmc.org/articles/PMC2925892?pdf=render |
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