Deléhouzée Sophie, Yoshikawa Tatsufumi, Sawa Chika, Sawada Jun-Ichi, Ito Takumi, Omori Masashi, Wada Tadashi, Yamaguchi Yuki, Kabe Yasuaki, Handa Hiroshi
Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan.
Genes Cells. 2005 Jul;10(7):717-31. doi: 10.1111/j.1365-2443.2005.00873.x.
Muscle cell differentiation, or myogenesis, is a well-characterized process and involves the expression of specific sets of genes in an orderly manner. A prerequisite for myogenesis is the exit from the cell cycle, which is associated with the up-regulation of the tumor suppressor Rb. In this study, we set to investigate the regulatory mechanism of the Rb promoter that allows adequate up-regulation in differentiating myoblasts. We report that Rb expression is regulated by the transcription factors GABP, HCF-1 and YY1. Before induction of differentiation, Rb is expressed at a low level and GABP and YY1 are both present on the promoter. YY1, which exerts an inhibitory effect on Rb expression, is removed from the promoter as cells advance through myogenesis and translocates from the nucleus to the cytoplasm. On the other hand, upon induction of differentiation, the GABP cofactor HCF-1 is recruited to and coactivates the promoter with GABP. RNAi-mediated knock-down of HCF-1 results in inhibition of Rb up-regulation as well as myotube formation. These results indicate that the Rb promoter is subject to regulation by positive and negative factors and that this intricate activation mechanism is critical to allow the accurate Rb gene up-regulation observed during myogenesis.
肌肉细胞分化，即肌生成，是一个已被充分表征的过程，涉及特定基因集按顺序表达。肌生成的一个先决条件是退出细胞周期，这与肿瘤抑制因子Rb的上调相关。在本研究中，我们着手研究Rb启动子的调控机制，该机制能在分化的成肌细胞中实现充分上调。我们报告称，Rb的表达受转录因子GABP、HCF-1和YY1调控。在诱导分化之前，Rb低水平表达，GABP和YY1均存在于启动子上。YY1对Rb表达起抑制作用，随着细胞在肌生成过程中进展，它从启动子上移除并从细胞核转移至细胞质。另一方面，在诱导分化时，GABP辅因子HCF-1被招募至启动子并与GABP共同激活启动子。RNAi介导的HCF-1敲低导致Rb上调以及肌管形成受到抑制。这些结果表明，Rb启动子受到正负因子的调控，且这种复杂的激活机制对于在肌生成过程中观察到的Rb基因准确上调至关重要。
