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Departments of Oncology [M. B. K., O. O., D. S., B. V.] and Physiology [R. W. C.], The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
The inhibition of replicative DNA synthesis that follows DNA damage may be critical for avoiding genetic lesions that could contribute to cellular transformation. Exposure of ML-1 myeloblastic leukemia cells to non-lethal doses of the DNA damaging agents,
-irradiation or actinomycin D, causes a transient inhibition of replicative DNA synthesis via both G1 and G2 arrests. Levels of p53 protein in ML-1 cells and in proliferating normal bone marrow myeloid progenitor cells increase and decrease in temporal association with the G1 arrest. In contrast, the S-phase arrest of ML-1 cells caused by exposure to the anti-metabolite, cytosine arabinoside, which does not directly damage DNA, is not associated with a significant change in p53 protein levels. Caffeine treatment blocks both the G1 arrest and the induction of p53 protein after
-irradiation, thus suggesting that blocking the induction of p53 protein may contribute to the previously observed effects of caffeine on cell cycle changes after DNA damage. Unlike ML-1 cells and normal bone marrow myeloid progenitor cells, hematopoietic cells that either lack p53 gene expression or overexpress a mutant form of the p53 gene do not exhibit a G1 arrest after
-irradiation; however, the G2 arrest is unaffected by the status of the p53 gene. These results suggest a role for the wild-type p53 protein in the inhibition of DNA synthesis that follows DNA damage and thus suggest a new mechanism for how the loss of wild-type p53 might contribute to tumorigenesis.
1 This work was supported in part by grants from the American Cancer Society (CD-434 to R. W. C. and Maryland Division to M. B. K.), the Preuss Foundation, and NIH (CA 43460 to B. V. and CA 09071 to D. S.). M. B. K. is a Scholar of the Children's Cancer Foundation and a W. M. Keck Foundation Scholar.
2 To whom requests for reprints should be addressed, at: Oncology 3–120, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21205.
Received 7/ 2/91. Accepted 9/18/91.
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S. Mattiussi, P. Turrini, L. Testolin, F. Martelli, G. Zaccagnini, A. Mangoni, L. M Barlucchi, A. Antonini, B. Illi, C. Cirielli, et al. p21Waf1/Cip1/Sdi1 mediates shear stress-dependent antiapoptotic function Cardiovasc Res, March 1, 2004; 61(4): 693 - 704. [Abstract] [Full Text] [PDF] |
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F. Mancini, F. Gentiletti, M. D'Angelo, S. Giglio, S. Nanni, C. D'Angelo, A. Farsetti, G. Citro, A. Sacchi, A. Pontecorvi, et al. MDM4 (MDMX) Overexpression Enhances Stabilization of Stress-induced p53 and Promotes Apoptosis J. Biol. Chem., February 27, 2004; 279(9): 8169 - 8180. [Abstract] [Full Text] [PDF] |
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L. A. Scott, J. K. Vass, E. K. Parkinson, D. A. F. Gillespie, J. N. Winnie, and B. W. Ozanne Invasion of Normal Human Fibroblasts Induced by v-Fos Is Independent of Proliferation, Immortalization, and the Tumor Suppressors p16INK4a and p53 Mol. Cell. Biol., February 15, 2004; 24(4): 1540 - 1559. [Abstract] [Full Text] [PDF] |
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I. Martin-Burriel, N. O. Roome, O. Dorchies, and A. Prenez Histopathological and Molecular Changes During Apoptosis Produced by 7H-Dibenzo[c,g]-Carbazole in Mouse Liver Toxicol Pathol, February 1, 2004; 32(2): 202 - 211. [Abstract] [PDF] |
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E. S. Stavridi and T. D. Halazonetis p53 and stress in the ER Genes & Dev., February 1, 2004; 18(3): 241 - 244. [Full Text] [PDF] |
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M.-Y. J. Lam, K. K. Youngren, and J. H. Nadeau Enhancers and Suppressors of Testicular Cancer Susceptibility in Single- and Double-Mutant Mice Genetics, February 1, 2004; 166(2): 925 - 933. [Abstract] [Full Text] [PDF] |
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P H Constable, J G Crowston, N L Occleston, and P T Khaw The effects of single doses of {beta} radiation on the wound healing behaviour of human Tenon's capsule fibroblasts Br J Ophthalmol, February 1, 2004; 88(2): 169 - 173. [Abstract] [Full Text] [PDF] |
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D. Goldschneider, E. Blanc, G. Raguenez, M. Barrois, A. Legrand, G. Le Roux, H. Haddada, J. Benard, and S. Douc-Rasy Differential response of p53 target genes to p73 overexpression in SH-SY5Y neuroblastoma cell line J. Cell Sci., January 15, 2004; 117(2): 293 - 301. [Abstract] [Full Text] [PDF] |
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A. C. Joerger, M. D. Allen, and A. R. Fersht Crystal Structure of a Superstable Mutant of Human p53 Core Domain: INSIGHTS INTO THE MECHANISM OF RESCUING ONCOGENIC MUTATIONS J. Biol. Chem., January 9, 2004; 279(2): 1291 - 1296. [Abstract] [Full Text] [PDF] |
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N. Takeyama, T. Tanaka, T. Yabuki, and T. Nakatani The Involvement of p53 in Paraquat-Induced Apoptosis in Human Lung Epithelial-Like Cells International Journal of Toxicology, January 1, 2004; 23(1): 33 - 40. [Abstract] [Full Text] [PDF] |
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L. Xia, A. Paik, and J. J. Li p53 Activation in Chronic Radiation-Treated Breast Cancer Cells: Regulation of MDM2/p14ARF Cancer Res., January 1, 2004; 64(1): 221 - 228. [Abstract] [Full Text] [PDF] |
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I. Zurer, L. J. Hofseth, Y. Cohen, M. Xu-Welliver, S. P. Hussain, C. C. Harris, and V. Rotter The role of p53 in base excision repair following genotoxic stress Carcinogenesis, January 1, 2004; 25(1): 11 - 19. [Abstract] [Full Text] [PDF] |
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A. Chavez-Reyes, J. M. Parant, L. L. Amelse, R. M. de Oca Luna, S. J. Korsmeyer, and G. Lozano Switching Mechanisms of Cell Death in mdm2- and mdm4-null Mice by Deletion of p53 Downstream Targets Cancer Res., December 15, 2003; 63(24): 8664 - 8669. [Abstract] [Full Text] [PDF] |
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J. L. Bronder and R. G. Moran A Defect in the p53 Response Pathway Induced by de Novo Purine Synthesis Inhibition J. Biol. Chem., December 5, 2003; 278(49): 48861 - 48871. [Abstract] [Full Text] [PDF] |
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S. Macip, M. Igarashi, P. Berggren, J. Yu, S. W. Lee, and S. A. Aaronson Influence of Induced Reactive Oxygen Species in p53-Mediated Cell Fate Decisions Mol. Cell. Biol., December 1, 2003; 23(23): 8576 - 8585. [Abstract] [Full Text] [PDF] |
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I. Hernandez, L. A. Maddison, Y. Wei, F. DeMayo, T. Petras, B. Li, J. R. Gingrich, J. M. Rosen, and N. M. Greenberg Prostate-Specific Expression of p53R172L Differentially Regulates p21, Bax, and mdm2 to Inhibit Prostate Cancer Progression and Prolong Survival Mol. Cancer Res., December 1, 2003; 1(14): 1036 - 1047. [Abstract] [Full Text] [PDF] |
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C. Jung, M. Motwani, J. Kortmansky, F. M. Sirotnak, Y. She, M. Gonen, A. Haimovitz-Friedman, and G. K. Schwartz The Cyclin-Dependent Kinase Inhibitor Flavopiridol Potentiates {gamma}-Irradiation-Induced Apoptosis in Colon and Gastric Cancer Cells Clin. Cancer Res., December 1, 2003; 9(16): 6052 - 6061. [Abstract] [Full Text] [PDF] |
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B. Freie, X. Li, S. L. M. Ciccone, K. Nawa, S. Cooper, C. Vogelweid, L. Schantz, L. S. Haneline, A. Orazi, H. E. Broxmeyer, et al. Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis Blood, December 1, 2003; 102(12): 4146 - 4152. [Abstract] [Full Text] [PDF] |
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