Harada H, Kondo T, Ogawa S, Tamura T, Kitagawa M, Tanaka N, Lamphier M S, Hirai H, Taniguchi T
Institute for Molecular and Cellular Biology, Osaka University, Japan.
Oncogene. 1994 Nov;9(11):3313-20.
The transcription factor IRF-1 has been shown to function as a tumor suppressor. Here we report that a significant proportion of the IRF-1 mRNA detected in normal human hematopoietic cells and cultured cell lines lacks exon 2 (containing the AUG initiation codon) and 3 as a result of exon skipping. Surprisingly, when we examined the bone marrow and peripheral mononuclear cells from patients with myelodysplastic syndrome (MDS) or leukemia secondary to MDS, we could still detect the exon-skipped form but little or none of the intact IRF-1 mRNA. This appears to be the result of accelerated exon skipping since we could find no mutations within the exons and splicing junctions from these patients. The exon-skipped form of IRF-1 lacking exons 2 and 3 displayed neither DNA binding nor tumor suppressive activities. Thus this accelerated exon skipping may cause the inactivation of IRF-1 and thereby contribute to the development of human hematopoietic malignancies.
转录因子IRF-1已被证明具有肿瘤抑制功能。在此我们报告，在正常人造血细胞和培养细胞系中检测到的相当一部分IRF-1 mRNA由于外显子跳跃而缺失外显子2（包含AUG起始密码子）和外显子3。令人惊讶的是，当我们检查骨髓增生异常综合征（MDS）患者或继发于MDS的白血病患者的骨髓和外周血单个核细胞时，我们仍然可以检测到外显子跳跃形式，但完整的IRF-1 mRNA很少或几乎没有。这似乎是外显子跳跃加速的结果，因为我们在这些患者的外显子和剪接连接处未发现突变。缺少外显子2和3的IRF-1外显子跳跃形式既不显示DNA结合活性也不显示肿瘤抑制活性。因此，这种加速的外显子跳跃可能导致IRF-1失活，从而促进人类造血系统恶性肿瘤的发生。
