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The regulation of the cytokine gene expression in cell growth and differentiation

细胞生长和分化过程中细胞因子基因表达的调节

基本信息

批准号：
04670288
负责人：
HARADA Hisashi
金额：
$ 1.41万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1994
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04670288/
关键词：
Interferon gene network gene targetting aniviral tumor supressor MDS leukemia IRF‐2 転写因子 IRF 細胞増殖癌化白血病 MDS ノックアウトマウス

项目摘要

Two structurally related transcription factors, IRF-1 and IRF-2 were originally identified as regulators of the interferon (IFN) system. It has been shown that IRF-1 functions as an activator for the type I IFN genes and some IFN-inducible genes, whereas IRF-2 represses the effect of IRF-1 by competing for binding to the same DNA sequence elements (IRF-E_8). We demonstrated a role for IRF-1 as a tumor suppressor ; overexpression of the repressor IRF-2 in NIH3T3 cells causes cell transformation and this cell transformation is suppressed by concomitant overexpression of the activator IRF-1. To examine further the role of IRF-1 and IRF-2 in vivo, we genereted mice with a null mutation in the IRF-1 gene or IRF-2 gene by gene targetting. We demonstrate that (i) infection with BCG was more severe in IRF-1^<-/-> mice than in wild-type mice ; (ii) the inhibition of encephalimyocarditis virus (EMCV) replication by IFN was impared in cells from IRF-1^<-/-> mice and these mice were less resistant than wild-type mice to EMCV infection ; (iii) primary embryonic fibroblasts (EFs) with a null mutation in the IRF-1 gene (IRF-1^<-/-> mice) are susceptible to transformation by an activated form of c-Ha-ras, a property also seen in the EFs from p53^<-/-> mice, but not in wild-type EFs. Thus, IRF-1 contributes to antibacterial, antiviral, and antitumor functions. The human IRF-1 gene has been mapped to 5q31.1. It has been demonstrated that one or both human IRF-1 alleles were deleted in MDS and leukemia chracterrized by 5q abberations. We also found that the accelerated exon skipping of human IRF-1 gene may cause the inactivation of IRF-1 and thereby contribute to the development of human hematopoietic malignancies.

两个结构上相关的转录因子IRF-1和IRF-2最初被确定为干扰素系统的调节因子。已有研究表明，IRF-1可以激活I型干扰素基因和一些干扰素诱导基因，而IRF-2通过竞争结合相同的DNA序列元件(IRF-E_8)来抑制IRF-1的作用。我们证明了IRF-1作为肿瘤抑制因子的作用；在NIH3T3细胞中过表达抑制因子IRF-2会导致细胞转化，而伴随的激活因子IRF-1的过表达会抑制这种细胞转化。为了进一步研究IRF-1和IRF-2在体内的作用，我们通过基因打靶的方法产生了IRF-1基因或IRF-2基因零突变的小鼠。我们发现：(I)IRF-1；-/-&gt；小鼠感染卡介苗比野生型小鼠更为严重；(Ii)在IRF-1；-/-&gt；小鼠细胞中，干扰素对脑心肌炎病毒(EMCV)复制的抑制作用受到损害，并且这些小鼠对EMCV感染的抵抗力低于野生型小鼠；(Iii)IRF-1基因零突变的原代胚胎成纤维细胞(EFS)。小鼠)易受c-Ha-ras活化形式的影响，这一特性也见于P53^-lt；-/-&gt；小鼠的EFS中，但在野生型EFS中则不然。因此，IRF-1具有抗菌、抗病毒和抗肿瘤功能。人类IRF-1基因已定位于5q31.1。已有研究表明MDS和白血病患者中有一个或两个人的IRF-1等位基因缺失。我们还发现，人类IRF-1基因外显子的加速跳跃可能导致了IRF-1的失活，从而促进了人类血液系统恶性肿瘤的发展。