Kröger Andrea, Stirnweiss Anja, Pulverer Julia Elisabeth, Klages Katjana, Grashoff Martina, Reimann Jörg, Hauser Hansjörg
Department of Gene Regulation and Differentiation, Helmholtz Center for Infection Research, Braunschweig, Germany.
Cancer Res. 2007 Apr 1;67(7):2972-81. doi: 10.1158/0008-5472.CAN-06-3564.
IFNs have been ascribed to mediate antitumor effects. IFN regulatory factor-1 (IRF-1) is a major target gene of IFNs. It inhibits cell proliferation and oncogenic transformation. Here, we show that 60% of all mRNAs deregulated by oncogenic transformation mediated by c-myc and H-ras are reverted to the expression levels of nontransformed cells by IRF-1. These include cell cycle-regulating genes. An indirect target is cyclin D1. Activation of IRF-1 decreased cyclin D1 expression and cyclin-dependent kinase 4 kinase activity concomitant with change in the levels of hyperphosphorylated retinoblastoma protein. These effects are mediated by inhibition of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway and a transcriptional repression of cyclin D1. As shown by in vitro assays and tumor growth in nude mice, IRF-1-mediated effects on cell cycle progression were found to be overridden by ectopic expression of cyclin D1. Conversely, decrease of cyclin D1 by RNA interference experiments prevents transformation and tumor growth. The data show that cyclin D1 is a key target for IRF-1-mediated tumor-suppressive effects.
干扰素被认为可介导抗肿瘤作用。干扰素调节因子-1（IRF-1）是干扰素的主要靶基因。它可抑制细胞增殖和致癌转化。在此，我们发现，由c-myc和H-ras介导的致癌转化所导致的所有失调mRNA中，60%可通过IRF-1恢复至未转化细胞的表达水平。这些基因包括细胞周期调节基因。细胞周期蛋白D1是一个间接靶点。IRF-1的激活降低了细胞周期蛋白D1的表达及细胞周期蛋白依赖性激酶4的激酶活性，同时伴有视网膜母细胞瘤蛋白过度磷酸化水平的改变。这些效应是通过抑制丝裂原活化蛋白激酶激酶/细胞外信号调节激酶途径以及对细胞周期蛋白D1的转录抑制来介导的。如体外实验和裸鼠肿瘤生长实验所示，发现细胞周期蛋白D1的异位表达可抵消IRF-1对细胞周期进程的影响。相反，通过RNA干扰实验降低细胞周期蛋白D1可阻止转化和肿瘤生长。数据表明，细胞周期蛋白D1是IRF-1介导的肿瘤抑制作用的关键靶点。
