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% 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.
Nantajit
Danupon
D
Department of Radiation Oncology, University of California Davis, Sacramento, California, United States of America.
Fan
Ming
M
Duru
Nadire
N
Wen
Yunfei
Y
Reed
John C
JC
Li
Jian Jian
JJ
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000528:radiation effects; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D056744:Cyclin B1 / Q000378:metabolism*; D004249:DNA Damage; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D013379:Substrate Specificity; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
D000970:Antineoplastic Agents; D056744:Cyclin B1; D016159:Tumor Suppressor Protein p53; D012694:Serine; D000255:Adenosine Triphosphate; D016203:CDC2 Protein Kinase
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