Radiation-induced anti-apoptotic response by Cdk1-mediated mitochondrial p53 phosphorylation

Tumor radioadaptive resistance during the course of radiation therapy presents a challenge for successful tumor control and potentially leads to tumor recurrence. Several genes and molecular mechanisms have been identified to be targets for tumor sensitization including p53, which has been consistently believed to induce cellular intrinsic apoptosis since approximately 50% of human cancers contain mutations in the p53 gene. Although the pro-apoptotic functions of p53 have been well defined in preventing genomic instability and cell transformation, recent studies have shown that p53 also contributes to a pro-survival advantage of tumor cells under DNA damage conditions. This fact has raised a critical question in radiation therapy for the remaining 50% human cancers with intact p53. This thesis explores the mitochondrial localization of the cell cycle regulator cyclin B1/Cdk1 and its regulation of mitochondrial p53 functions. Results demonstrate that under the stress of ionizing radiation mitochondrial translocation of cyclin B1/Cdk1 kinase is greatly enhanced which leads to the phosphorylation of mitochondrial p53 at Ser-315 residue. The phosphorylation not only inhibits the pro-apoptotic functions of p53 in mitochondria, but also provides mitochondrial integrity and subsequent anti-apoptotic response. These results present a unique nuclear-to-mitochondrial signal and raise a critical question of exploiting p53 to induce tumor apoptosis for the cure of cancer