Vail Mary E, Chaisson Michelle L, Thompson James, Fausto Nelson
Department of Pathology, University of Washington, Seattle, Washington, WA 98195-7705, USA.
Oncogene. 2002 Feb 28;21(10):1548-55. doi: 10.1038/sj.onc.1205212.
Bcl-2 is the prototype of a family of genes that prevent apoptosis. However, several reports indicate that Bcl-2 may also act as a cell cycle modulator. In several human tumors, Bcl-2 expression correlates with a more favorable prognosis and lower tumor proliferative activity. We have shown that Bcl-2 expression delays liver tumor development in transgenic mice even when the gene is turned on shortly before the time of tumor development. We hypothesized that Bcl-2 may delay liver tumorigenesis by interfering with hepatocyte proliferation. To test whether Bcl-2 expression may act on hepatocyte replication we studied liver regeneration in Bcl-2 transgenic mice and wild-type littermates. DNA replication was delayed by approximately 8 h in Bcl-2 transgenic mice compared to the timing of the response in wild-type littermates. Cyclin D expression showed no alterations in the regenerating liver of Bcl-2 transgenic mice. In contrast, there was a delay in the expression of p107, cyclin E and in the activity of cyclin E/cdk 2 activity. These results show that Bcl-2 expression delays cell cycle progression in hepatocytes and suggests that it acts at a step involving cyclin E and p107.
Bcl-2是一组防止细胞凋亡的基因家族的原型。然而，有几份报告表明，Bcl-2也可能作为一种细胞周期调节剂发挥作用。在几种人类肿瘤中，Bcl-2的表达与更有利的预后和更低的肿瘤增殖活性相关。我们已经表明，即使在肿瘤发生前不久才开启该基因，Bcl-2的表达也会延缓转基因小鼠肝脏肿瘤的发展。我们推测，Bcl-2可能通过干扰肝细胞增殖来延缓肝脏肿瘤的发生。为了测试Bcl-2的表达是否可能作用于肝细胞复制，我们研究了Bcl-2转基因小鼠和野生型同窝小鼠的肝脏再生。与野生型同窝小鼠的反应时间相比，Bcl-2转基因小鼠的DNA复制延迟了约8小时。在Bcl-2转基因小鼠再生肝脏中，细胞周期蛋白D的表达没有变化。相反，p107、细胞周期蛋白E的表达以及细胞周期蛋白E/细胞周期蛋白依赖性激酶2的活性出现延迟。这些结果表明，Bcl-2的表达延缓了肝细胞的细胞周期进程，并表明它作用于涉及细胞周期蛋白E和p107的步骤。
