Kolb Sebastian, Fritsch Ralph, Saur Dieter, Reichert Maximilian, Schmid Roland M, Schneider Günter
Department of Internal Medicine II, Technical University of Munich, Ismaninger, Munich, Germany.
Cancer Res. 2007 May 15;67(10):4679-86. doi: 10.1158/0008-5472.CAN-06-3308.
The HMGA1 proteins act as architectural transcription factors and are involved in the regulation of genes important in the process of carcinogenesis. Although HMGA1 proteins are overexpressed in most types of cancer, signaling circuits regulated by HMGA1 are not clarified in detail. In this study, we show that HMGA1 proteins promote proliferation of pancreatic cancer cells by accelerating G(1) phase progression. Transfection of HMGA1-specific small interfering RNA (siRNA) activates the RB-dependent G(1)-phase checkpoint due to the impaired expression of cyclin D1. Down-regulation of cyclin D1 after the HMGA1 knockdown is due to translational control and involves the repressor of the eukaryotic translation initiation factor 4E (eIF4E) 4E-BP1. We show that 4E-BP1 and cyclin D1 act downstream of the insulin receptor (IR) in pancreatic cancer cells. At the molecular level transcription of the IR is controlled by a CAAT/enhancer binding protein beta (C/EBPbeta)/HMGA1 complex. Together, this work defines a novel pathway regulated by HMGA1, which contributes to the proliferation of pancreatic cancer cells.
HMGA1蛋白作为一种结构转录因子，参与致癌过程中重要基因的调控。尽管HMGA1蛋白在大多数癌症类型中均有过表达，但由HMGA1调控的信号通路尚未得到详细阐明。在本研究中，我们发现HMGA1蛋白通过加速G1期进程促进胰腺癌细胞的增殖。转染HMGA1特异性小干扰RNA（siRNA）可激活RB依赖的G1期检查点，这是由于细胞周期蛋白D1的表达受损所致。HMGA1敲低后细胞周期蛋白D1的下调是由于翻译控制，并且涉及真核翻译起始因子4E（eIF4E）的抑制剂4E-BP1。我们发现4E-BP1和细胞周期蛋白D1在胰腺癌细胞中位于胰岛素受体（IR）的下游发挥作用。在分子水平上，IR的转录受CCAAT/增强子结合蛋白β（C/EBPβ）/HMGA1复合物的控制。总之，这项工作定义了一条由HMGA1调控的新途径，该途径有助于胰腺癌细胞的增殖。
