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

两个结构相关的转录因子IRF-1和IRF-2最初被确定为干扰素（IFN）系统的调节因子。研究表明，IRF-1作为I型IFN基因和一些IFN诱导基因的激活剂，而IRF-2通过竞争结合相同的DNA序列元件来抑制IRF-1的作用（IRF-E_8）。我们证明了IRF-1作为肿瘤抑制因子的作用；NIH3T3细胞中抑制因子IRF-2的过表达导致细胞转化，而这种细胞转化被伴随的激活因子IRF-1的过表达所抑制。为了进一步研究IRF-1和IRF-2在体内的作用，我们通过基因靶向产生了IRF-1基因或IRF-2基因零突变的小鼠。我们证明(i)与野生型小鼠相比，IRF-1^<-/->小鼠卡介苗感染更为严重；（ii） IFN对脑脊肌心炎病毒（EMCV）复制的抑制作用在IRF-1^<-/->小鼠细胞中受损，这些小鼠对EMCV感染的抗性低于野生型小鼠；（iii） IRF-1基因无突变的原代胚胎成纤维细胞（IRF-1^<-/->小鼠）易被活化形式的c-Ha-ras转化，这一特性也见于p53^<-/->小鼠的原代胚胎成纤维细胞，但在野生型EFs中不存在。因此，IRF-1有助于抗菌、抗病毒和抗肿瘤功能。人类IRF-1基因已定位到5q31.1。已经证明，在MDS和以5q畸变为特征的白血病中，一个或两个人类IRF-1等位基因被删除。我们还发现，人类IRF-1基因外显子的加速跳跃可能导致IRF-1失活，从而促进人类造血恶性肿瘤的发展。

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.