Wu An, Tu Xiao, Prisco Marco, Baserga Renato
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
J Biol Chem. 2005 Jan 28;280(4):2863-72. doi: 10.1074/jbc.M406138200. Epub 2004 Nov 8.
The upstream binding factor 1 (UBF1) is one of the proteins in a complex that regulates the activity of RNA polymerase I, which controls the rate of ribosomal RNA (rRNA) synthesis. We have shown previously that insulin receptor substrate-1 (IRS-1) can translocate to the nuclei and nucleoli of cells and bind UBF1. We report here that activation of the type I insulin-like growth factor receptor (IGF-IR) by IGF-I increases transcription from the ribosomal DNA (rDNA) promoter in both myeloid cells and mouse fibroblasts. The increased activity of the rDNA promoter is accompanied by increased phosphorylation of UBF1, a requirement for UBF1 activation. Phosphorylation occurs on a number of UBF1 peptides, most prominently on the highly acidic, serine-rich C terminus. In myeloid cells (but not in mouse embryo fibroblasts) IRS-1 signaling stabilizes the levels of UBF1 protein. These findings demonstrate that IGF-IR signaling can increase the activity of UBF1 and transcription from the rDNA promoter, providing one explanation for the reported effects of the IGF/IRS-1 axis on cell and body size in animals and cells in culture.
上游结合因子1（UBF1）是调节RNA聚合酶I活性的复合物中的一种蛋白质，RNA聚合酶I控制核糖体RNA（rRNA）的合成速率。我们之前已经表明，胰岛素受体底物-1（IRS-1）可以转移到细胞核和核仁并与UBF1结合。我们在此报告，IGF-I对I型胰岛素样生长因子受体（IGF-IR）的激活增加了髓系细胞和小鼠成纤维细胞中核糖体DNA（rDNA）启动子的转录。rDNA启动子活性的增加伴随着UBF1磷酸化的增加，这是UBF1激活的必要条件。磷酸化发生在多个UBF1肽段上，最显著的是在高度酸性、富含丝氨酸的C末端。在髓系细胞中（但不在小鼠胚胎成纤维细胞中），IRS-1信号稳定UBF1蛋白的水平。这些发现表明，IGF-IR信号可以增加UBF1的活性和rDNA启动子的转录，为报道的IGF/IRS-1轴对动物和培养细胞中的细胞和体型的影响提供了一种解释。
