MxA overexpression reveals a common genetic link in four Fanconi anemia complementation groups.
MxA overexpression reveals a common genetic link in four Fanconi anemia complementation groups.
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MxA 过度表达揭示了四个范可尼贫血互补组中常见的遗传联系。
DOI：
10.1172/jci119836
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Youssoufian,H
中科院分区：
文献类型：
--
作者：
Li,Y;Youssoufian,H
范可尼贫血（FA）由一组至少五种常染色体隐性遗传疾病组成，这些疾病具有临床（例如，出生缺陷和造血衰竭）和细胞（例如，对交联剂的敏感性和对凋亡的倾向性）的特征。然而，这些群体之间的共同发病联系尚未建立。为了鉴定FA中改变的遗传途径并表征共享的分子缺陷，我们使用mRNA差异显示来分离FA细胞中改变表达模式的基因。在这里，我们报告的干扰素诱导基因，MxA的表达，是高度上调的FA互补组A，B，C和D的细胞，但它被抑制在FA组C细胞补充野生型FAC cDNA，以及在非FA细胞。转录后机制，而不是转录诱导似乎占MxA过表达。MxA在Hep3B细胞中的强制表达增强了它们对丝裂霉素C的敏感性并诱导凋亡，类似于FA表型。因此，MxA是FAC的下游靶标，并且是在多个FA互补组中待鉴定的第一个遗传标记。这些数据表明，FA亚型汇聚到一个最终的共同途径，这是密切相关的干扰素信号传导机制。该通路的组成性活性可以解释FA的许多表型特征，特别是骨髓衰竭的发病机制。
Fanconi anemia (FA) consists of a group of at least five autosomal recessive disorders that share both clinical (e.g., birth defects and hematopoietic failure) and cellular (e.g., sensitivity to cross-linking agents and predisposition to apoptosis) features with each other. However, a common pathogenetic link among these groups has not been established. To identify genetic pathways that are altered in FA and characterize shared molecular defects, we used mRNA differential display to isolate genes that have altered expression patterns in FA cells. Here, we report that the expression of an interferon-inducible gene, MxA, is highly upregulated in cells of FA complementation groups A, B, C, and D, but it is suppressed in FA group C cells complemented with wild-type FAC cDNA as well as in non-FA cells. A posttranscriptional mechanism rather than transcriptional induction appears to account for MxA overexpression. Forced expression of MxA in Hep3B cells enhances their sensitivity to mitomycin C and induces apoptosis, similar to the FA phenotype. Thus, MxA is a downstream target of FAC and is the first genetic marker to be identified among multiple FA complementation groups. These data suggest that FA subtypes converge onto a final common pathway, which is intimately related to the interferon signaling mechanism. Constitutive activity of this pathway may explain a number of the phenotypic features of FA, particularly the pathogenesis of bone marrow failure.