Matsui Takaaki, Kinoshita Taisei, Hirano Toshio, Yokota Takashi, Miyajima Atsushi
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
J Biol Chem. 2002 Sep 27;277(39):36167-73. doi: 10.1074/jbc.M203184200. Epub 2002 Jul 29.
As the expression of cyclin D1 is induced during liver regeneration and also in hepatic tumor cells, cyclin D1 is likely to play an important role in the proliferation and transformation of hepatocytes. However, the role of cyclin D1 in liver development remains unknown. Here we show that the expression of D-type cyclins including cyclin D1, D2, and D3 is down-regulated along with liver development. In addition, oncostatin M (OSM), an interleukin-6 family cytokine, down-regulated the expression of cyclin D1 and D2 in a primary culture of fetal hepatocytes in which OSM induces hepatic differentiation. Ectopic expression of receptor mutants defective in the activation of either STAT3 or SHP-2/Ras indicated that the down-regulation of D1 and D2 cyclins by OSM was mediated by STAT3 but not by SHP-2/Ras. Consistently, expression of dominant negative STAT3 but not Ras relieved OSM-induced suppression of cyclin D expression. Activation of STAT3 in fetal hepatocytes of transgenic mice expressing the STAT3-estrogen receptor fusion protein by 4-hydroxytamoxifen resulted in the suppression of cyclin D1 and D2 expression. These results indicate that STAT3 activation is necessary and sufficient for down-regulation of D1 and D2 cyclins in fetal hepatocytes. Furthermore, STAT3-C, a constitutively active form of STAT3, suppressed transcription of the cyclin D1 promoter in fetal hepatocytes, whereas it activated the transcription in hepatic tumor cells, huH7 and HepG2. Thus, STAT3-mediated down-regulation of cyclin D expression is rather specific to fetal hepatocytes that are undergoing maturation processes including a reduction of their proliferation potential.
由于细胞周期蛋白D1的表达在肝脏再生过程中以及肝肿瘤细胞中均被诱导，因此细胞周期蛋白D1可能在肝细胞的增殖和转化中发挥重要作用。然而，细胞周期蛋白D1在肝脏发育中的作用尚不清楚。在此我们表明，包括细胞周期蛋白D1、D2和D3在内的D型细胞周期蛋白的表达随着肝脏发育而下调。此外，制瘤素M（OSM），一种白细胞介素-6家族细胞因子，在OSM诱导肝细胞分化的原代胎儿肝细胞培养物中下调了细胞周期蛋白D1和D2的表达。在STAT3或SHP-2/Ras激活方面存在缺陷的受体突变体的异位表达表明，OSM对D1和D2细胞周期蛋白的下调是由STAT3介导的，而非由SHP-2/Ras介导。一致地，显性负性STAT3而非Ras的表达缓解了OSM诱导的细胞周期蛋白D表达的抑制。通过4-羟基他莫昔芬激活表达STAT3-雌激素受体融合蛋白的转基因小鼠胎儿肝细胞中的STAT3，导致细胞周期蛋白D1和D2表达的抑制。这些结果表明，STAT3激活对于胎儿肝细胞中D1和D2细胞周期蛋白的下调是必要且充分的。此外，STAT3-C，一种STAT3的组成型活性形式，在胎儿肝细胞中抑制细胞周期蛋白D1启动子的转录，而在肝肿瘤细胞huH7和HepG2中则激活转录。因此，STAT3介导的细胞周期蛋白D表达的下调对于正在经历包括增殖潜能降低在内的成熟过程的胎儿肝细胞具有相当的特异性。
