Beretta L, Gabbay M, Berger R, Hanash S M, Sonenberg N
Department of Biochemistry, McGill University, Montréal, Québec, Canada.
Oncogene. 1996 Apr 4;12(7):1593-6.
The transcription factor IRF-1 (interferon regulatory factor 1) is an activator of type I interferon and interferon-inducible genes. IRF-1 manifests tumor suppressor activity. Its overexpression results in inhibition of cell growth, and deletions of the IRF-1 gene were demonstrated in a number of human leukemias and myelodysplasias. Although the mechanism by which IRF-1 affects cell growth is unknown, it is believed that IRF-1 activates a set of genes that negatively regulate cell growth. The double-stranded RNA-dependent protein kinase (PKR), which is an interferon-inducible gene, contains a promoter element for the binding of IRF-1 and exhibits antiproliferative properties. Consequently, we investigated the role of IRF-1 in PKR expression. Here, we show that in IRF-1-deficient embryonic fibroblasts, PKR expression is reduced relative to wild-type cells. This result predicts diminished expression of PKR as a potential consequence of deletion of the IRF-1 gene in human leukemias. We show that cells of the human leukemic U937 cell line contain a deletion of one IRF-1 gene and express low levels of PKR. We demonstrate that upregulation of IRF-1 expression in U937 cells by transfection is sufficient to induce PKR expression. We also found a marked reduction in the expression of PKR in blood samples from two patients with myelodysplasias, carrying a deletion of chromosome 5q, a locus to which IRF-1 was mapped. These results show that IRF-1 activates PKR expression and suggest that loss of one allele of the IRF-1 gene is sufficient to affect PKR expression. Therefore, PKR is a strong candidate for a mediator of the tumor suppressor activity of IRF-1.
转录因子IRF-1（干扰素调节因子1）是I型干扰素和干扰素诱导基因的激活剂。IRF-1具有肿瘤抑制活性。其过表达会导致细胞生长受到抑制，并且在许多人类白血病和骨髓发育异常中都证实了IRF-1基因的缺失。尽管IRF-1影响细胞生长的机制尚不清楚，但据信IRF-1会激活一组对细胞生长起负调节作用的基因。双链RNA依赖性蛋白激酶（PKR）是一种干扰素诱导基因，它含有一个用于IRF-1结合的启动子元件，并具有抗增殖特性。因此，我们研究了IRF-1在PKR表达中的作用。在此，我们表明，在IRF-1缺陷的胚胎成纤维细胞中，与野生型细胞相比，PKR表达降低。这一结果预示着，在人类白血病中，IRF-1基因缺失可能会导致PKR表达减少。我们发现人类白血病U937细胞系的细胞中一个IRF-1基因缺失，且PKR表达水平较低。我们证明，通过转染上调U937细胞中IRF-1的表达足以诱导PKR表达。我们还发现，两名患有骨髓发育异常且5号染色体q臂缺失（IRF-1基因定位于该位点）的患者的血液样本中，PKR的表达显著降低。这些结果表明，IRF-1激活PKR表达，并提示IRF-1基因一个等位基因的缺失就足以影响PKR表达。因此，PKR是IRF-1肿瘤抑制活性介导因子的有力候选者。
