Overexpression of thioredoxin in Fanconi anemia fibroblasts prevents the cytotoxic and DNA damaging effect of mitomycin C and diepoxybutane

FEBS Letters

Schweiger, Manfred¹  Meißlitzer, Claudia¹  Ruppitsch, Werner¹  Hirsch-Kauffmann, Monica² 

[1] Institut für Biochemie, Freie Universität Berlin, Thielallee 63, 14195 Berlin-Dahlem, Germany;Institut für Medizinische Biologie und Humangenetik, Schöpfstraße 41, Universität Innsbruck, Innsbruck, Austria

关键词: Fanconi anemia;    DNA repair;    Oxidative stress;    Thioredoxin;    Nuclear factor kappa B;    ADF;    adult T cell leukemia derived factor;    Trx;    thioredoxin;    NF-κB;    nuclear factor kappa B;    FA;    Fanconi anemia;    ROI;    reactive oxygen intermediates;    MMC;    mitomycin C;    DEB;    diepoxybutane;   

DOI  :  10.1016/S0014-5793(97)01608-6

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Adult T cell leukemia derived factor (ADF)/thioredoxin (Trx) is known to be an important intracellular antioxidant involved in a number of redox reactions such as ribonucleotide reductase (RNR) as well as of tyrosinase. Since RNR is a key enzyme of nucleotide metabolism and DNA synthesis, a reduced Trx level would result in reduced enzymatic activity and cause DNA damage. Furthermore, Trx is considered to be an effective regulator of redox sensitive gene expression. The role of Trx in nucleotide metabolism and gene expression may be an explanation for increased chromosomal instability as well as hypersensitivity towards oxygen, ROI and ROI generating agents. The activity of tyrosinase, the key enzyme of melanin biosynthesis, is influenced by the thioredoxin level and by superoxide radicals. Low thioredoxin levels and high superoxide concentrations activate tyrosinase causing hyperpigmentation of the skin. In addition to the observed high superoxide concentration in Fanconi anemia (FA) patients, a low thioredoxin level might be responsible for the hyperpigmentation (café-au-lait spots) in this disease. We observed that overexpression of the thioredoxin cDNA in FA fibroblasts completely abolished the DNA damaging effects of mitomycin C and diepoxybutane and inhibited the constitutive activity of the nuclear factor κB (NF-κB) in SV40 transformed FA fibroblasts. However, spontaneous chromosomal breakage was not affected.

【 授权许可】

Unknown