The catalytic subunit of DNA-dependent protein kinase selectively regulates p53-dependent apoptosis but not cell-cycle arrest Journal Article
| Authors: | Wang, S.; Guo, M.; Ouyang, H.; Li, X.; Cordon-Cardo, C.; Kurimasa, A.; Chen, D. J.; Fuks, Z.; Clifton Ling, C.; Li, G. C. |
| Article Title: | The catalytic subunit of DNA-dependent protein kinase selectively regulates p53-dependent apoptosis but not cell-cycle arrest |
| Abstract: | DNA damage induced by ionizing radiation (IR) activates p53, leading to the regulation of downstream pathways that control cell-cycle progression and apoptosis. However, the mechanisms for the IR-induced p53 activation and the differential activation of pathways downstream of p53 are unclear. Here we provide evidence that the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) serves as an upstream effector for p53 activation in response to IR, linking DNA damage to apoptosis. DNA-PKcs knockout (DNA-PKcs-/-) mice were exposed to whole-body IR, and the cell-cycle and apoptotic responses were examined in their thymuses. Our data show that IR induction of apoptosis and Bax expression, both mediated via p53, was significantly suppressed in the thymocytes of DNA-PKcs-/- mice. In contrast, IR-induced cell-cycle arrest and p21 expression were normal. Thus, DNA-PKcs deficiency selectively disrupts p53-dependent apoptosis but not cell-cycle arrest. We also confirmed previous findings that p21 induction was attenuated and cell-cycle arrest was defective in the thymocytes of whole body-irradiated Atm-/- mice, but the apoptotic response was unperturbed. Taken together, our results support a model in which the upstream effectors DNA-PKcs and Atm selectively activate p53 to differentially regulate cell-cycle and apoptotic responses. Whereas Atm selects for cell-cycle arrest but not apoptosis, DNA-PKcs selects for apoptosis but not cell-cycle arrest. |
| Keywords: | signal transduction; controlled study; protein expression; dna-binding proteins; proto-oncogene proteins; nonhuman; flow cytometry; animal cell; animals; mice; mice, knockout; dna damage; cell cycle; dna repair; apoptosis; protein p53; animalia; thymus gland; protein-serine-threonine kinases; ionizing radiation; tumor suppressor protein p53; enzyme subunit; proto-oncogene proteins c-bcl-2; knockout mouse; whole-body irradiation; ataxia telangiectasia; in situ nick-end labeling; dna dependent protein kinase; dna-activated protein kinase; bcl-2-associated x protein; male; priority journal; article |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 97 |
| Issue: | 4 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2000-02-15 |
| Start Page: | 1584 |
| End Page: | 1588 |
| Language: | English |
| DOI: | 10.1073/pnas.97.4.1584 |
| PUBMED: | 10677503 |
| PROVIDER: | scopus |
| PMCID: | PMC26478 |
| DOI/URL: | |
| Notes: | Export Date: 18 November 2015 -- Source: Scopus |
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