Journal Article

Transition mutation in codon 248 of the <i>p53</i> tumor suppressor gene induced by reactive oxygen species and a nitric oxide-releasing compound

Anne-Christine Souici, Jovan Mirkovitch, Pierrette Hausel, Larry K.Keefer and Emanuela Felley-Bosco

in Carcinogenesis

Volume 21, issue 2, pages 281-287
Published in print February 2000 | ISSN: 0143-3334
Published online February 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.2.281
Transition mutation in codon 248 of the p53 tumor suppressor gene induced by reactive oxygen species and a nitric oxide-releasing compound

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Exposing the human bronchial epithelial cell line BEAS-2B to the nitric oxide (NO) donor sodium 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA/NO) at an initial concentration of 0.6 mM while generating superoxide ion at the rate of 1 μM/min with the hypoxanthine/xanthine oxidase (HX/XO) system induced C:G→T:A transition mutations in codon 248 of the p53 gene. This pattern of mutagenicity was not seen by `fish-restriction fragment length polymorphism/polymerase chain reaction' (fish-RFLP/PCR) on exposure to DEA/NO alone, however, exposure to HX/XO led to various mutations, suggesting that co-generation of NO and superoxide was responsible for inducing the observed point mutation. DEA/NO potentiated the ability of HX/XO to induce lipid peroxidation as well as DNA single- and double-strand breaks under these conditions, while 0.6 mM DEA/NO in the absence of HX/XO had no significant effect on these parameters. The results show that a point mutation seen at high frequency in certain common human tumors can be induced by simultaneous exposure to reactive oxygen species and a NO source.

Keywords: DEA/NO, sodium 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate; DHR 123, dihydrorhodamine 123; ENU, ethylnitrosourea; fish-RFLP/PCR, `fish-restriction fragment length polymorphism/polymerase chain reaction'; HPO, hydroperoxides; HX, hypoxanthine; iNOS, inducible nitric oxide synthase; MDA, malondialdehyde; NO, nitric oxide; NOS, nitric oxide synthases; RH 123, rhodamine 123; ROS, reactive oxygen species; SOD, superoxide dismutase; XO, xanthine oxidase.

Journal Article.  6687 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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