Repression of Fanconi anemia gene (FACC) expression inhibits growth of hematopoietic progenitor cells.
Repression of Fanconi anemia gene (FACC) expression inhibits growth of hematopoietic progenitor cells.
复制标题
抑制范可尼贫血基因 (FACC) 的表达会抑制造血祖细胞的生长。
DOI：
10.1172/jci117405
复制
发表时间：
1994
期刊：
影响因子：
--
通讯作者：
BagbyJr,GC
中科院分区：
文献类型：
--
作者：
Segal,GM;Magenis,RE;Brown,M;Keeble,W;Smith,TD;Heinrich,MC;BagbyJr,GC
骨髓衰竭是范可尼贫血 (FA) 的一贯特征，但尚不清楚骨髓衰竭是否是遗传突变的直接和特定结果，还是非特异性 DNA 损伤导致干细胞损失累积的结果。我们测试了 FA C 组互补基因 (FACC) 编码的蛋白质在造血过程中发挥调节作用的假设。我们将正常人淋巴细胞、骨髓细胞、内皮细胞和成纤维细胞暴露于与 FACC mRNA 碱基 -4 至 +14 互补的反义寡脱氧核苷酸 (ODN)。丝裂霉素 C 测定表明，反义 ODN（而非错义或有义 ODN）抑制淋巴细胞中的 FACC 基因表达。用反义ODN处理以序列特异性方式显着降低了骨髓细胞和淋巴细胞中FACC mRNA的细胞质水平。反义ODN剂量的增加逐渐抑制红细胞和粒细胞-巨噬细胞祖细胞的克隆生长，但不抑制成纤维细胞或内皮细胞的生长。反义ODN不抑制低密度骨髓细胞或骨髓源性成纤维细胞的生长因子基因表达。我们的结论是，虽然 FACC 基因产物在定义细胞对交联剂的耐受性方面发挥作用，但它也具有调节正常造血祖细胞的生长、分化和/或存活的功能。
Bone marrow failure is a consistent feature of Fanconi anemia (FA) but it is not known whether the bone marrow failure is a direct and specific result of the inherited mutation or a consequence of accumulated stem cell losses resulting from nonspecific DNA damage. We tested the hypothesis that the protein encoded by the FA group C complementing gene (FACC) plays a regulatory role in hematopoiesis. We exposed normal human lymphocytes, bone marrow cells, endothelial cells, and fibroblasts to an antisense oligodeoxynucleotide (ODN) complementary to bases -4 to +14 of FACC mRNA. The mitomycin C assay demonstrated that the antisense ODN, but not missense or sense ODNs, repressed FACC gene expression in lymphocytes. Treatment with the antisense ODN substantially reduced, in a sequence-specific fashion, cytoplasmic levels of FACC mRNA in bone marrow cells and lymphocytes. Escalating doses of antisense ODN increasingly inhibited clonal growth of erythroid and granulocyte-macrophage progenitor cells but did not inhibit growth of fibroblasts or endothelial cells. The antisense ODN did not inhibit growth factor gene expression by low density bone marrow cells or marrow-derived fibroblasts. We conclude that, while the FACC gene product plays a role in defining cellular tolerance to cross-linking agents, it also functions to regulate growth, differentiation, and/or survival of normal hematopoietic progenitor cells.Images