Loss of poly(ADP-ribose) polymerase-1 causes increased tumour latency in p53-deficient mice.
PARP-1-deficient mice display a severe defect in the base excision repair pathway leading to radiosensitivity and genomic instability. They are protected against necrosis induced by massive oxidative stress in various inflammatory processes. Mice lacking p53 are highly predisposed to malignancy resulting from defective cell cycle checkpoints, resistance to DNA damage-induced apoptosis as well as from upregulation of the iNOS gene resulting in chronic oxidative stress. Here, we report the generation of doubly null mutant mice. We found that tumour-free survival of parp-1(-/-)p53(-/-) mice increased by 50% compared with that of parp- 1(+/+)p53(-/-) mice. Tumour formation in nude mice injected with oncogenic parp-1(-/-)p53(-/-) fibroblasts was significantly delayed compared with parp-1(+/+)p53(-/-) cells. Upon gamma-irradiation, a partial restoration of S-phase radiosensitivity was found in parp-1(-/-)p53(-/-) primary fibroblasts compared with parp-1(+/+)p53(-/-) cells. In addition, iNOS expression and nitrite release were dramatically reduced in the parp-1(-/-)p53(-/-) mice compared with parp-1(+/+)p53(-/-) mice. The abrogation of the oxydated status of p53(-/-) cells, due to the absence of parp-1, may be the cause of the delay in the onset of tumorigenesis in parp-1(-/-)p53(-/-) mice.
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UPR 9003 du CNRS, Laboratoire Conventionné avec le Commissariat à l'Energie Atomique, Ecole Supérieure de Biotechnologie, Université Louis Pasteur de Strasbourg, Boulevard Sébastien Brant, F-67400 Illkirch, France.
Mark
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M
Oliver
F J
FJ
Huber
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A
de Murcia
G
G
Ménissier-de Murcia
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J
D000818:Animals; D002453:Cell Cycle / Q000502:physiology / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004260:DNA Repair; D018572:Disease-Free Survival; D005260:Female; D005347:Fibroblasts / Q000502:physiology / Q000528:radiation effects / Q000637:transplantation; D005720:Gamma Rays; D016158:Genes, p53; D011905:Genes, ras; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008819:Mice, Nude; D048629:Micronuclei, Chromosome-Defective / Q000235:genetics / Q000473:pathology / Q000648:ultrastructure; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D018384:Oxidative Stress; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D009573:Nitrites; D016159:Tumor Suppressor Protein p53; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011065:Poly(ADP-ribose) Polymerases