Kontou Maria, Adelfalk Caroline, Ramirez Maria Helena, Ruppitsch Werner, Hirsch-Kauffmann Monica, Schweiger Manfred
Institut für Biochemie, Freie Universität Berlin, Thielallee 63, D14195 Berlin, Germany.
Oncogene. 2002 Apr 4;21(15):2406-12. doi: 10.1038/sj.onc.1205299.
The cause of the molecular defect of Fanconi anemia (FA) remains unknown. Cells from patients with FA exert an elevated spontaneous chromosomal instability which is further triggered by mitomycin C. The induced lability is reduced by overexpression of thioredoxin which is not the case for spontaneous instability. However, both are eliminated by overexpression of thioredoxin cDNA with an added nuclear localization signal. This implies that thioredoxin is lacking in the nuclei of FA cells. The total thioredoxin content in all FA cells tested is reduced. The resultant lack of nuclear thioredoxin can be the explanation for the major symptomatology in FA. Since thioredoxin is known to be the reactive cofactor of ribonucleotid reductase its shortcoming reduces the supply of deoxyribonucleotides thus hindering the DNA and replication repair with resultant chromosomal breaks. Furthermore, depression of tyrosine hydroxylase, the key enzyme of melanine synthesis, could be the basis for the pathognomotic 'café au lait' spots of FA. The observation of thioredoxin reduction in FA cells permits insight into the molecular phathophysiology of FA.
范可尼贫血（FA）分子缺陷的原因尚不清楚。FA患者的细胞表现出较高的自发染色体不稳定性，丝裂霉素C可进一步引发这种不稳定性。硫氧还蛋白的过表达可降低诱导的不稳定性，但对自发不稳定性无效。然而，添加核定位信号的硫氧还蛋白cDNA的过表达可消除这两种不稳定性。这意味着FA细胞的细胞核中缺乏硫氧还蛋白。所有测试的FA细胞中的总硫氧还蛋白含量均降低。由此导致的核硫氧还蛋白缺乏可能是FA主要症状的原因。由于已知硫氧还蛋白是核糖核苷酸还原酶的反应性辅因子，其缺乏会减少脱氧核苷酸的供应，从而阻碍DNA和复制修复，导致染色体断裂。此外，酪氨酸羟化酶（黑色素合成的关键酶）的抑制可能是FA特征性“牛奶咖啡斑”的基础。观察到FA细胞中硫氧还蛋白减少有助于深入了解FA的分子病理生理学。
