Cell cycle and differentiation of secretin-secreting enteroendocrine cells by transcription factor BETA2.

在肠内分泌细胞中，分泌素激素的表达仅限于肠的不分裂绒毛部分，这意味着末端分化与细胞周期停滞有关，而分化在活跃的增殖细胞中受到抑制。我们以前已经证明，基本螺旋-环-螺旋蛋白，Beta2/NeuroD，除了增加促胰液素基因的表达外，还诱导细胞周期退出。一些对分化至关重要的转录因子被D细胞周期蛋白抑制。D细胞周期蛋白的抑制作用似乎与其对细胞周期的影响无关。我们发现，细胞周期蛋白D1抑制了促胰液素基因的β2/神经依赖性转录。对Cyclin盒突变体的检测表明，抑制与CDK4的激活无关。虽然细胞周期蛋白D1和β2在体内相互作用，但它们并不直接相互作用。细胞周期蛋白D1可以通过结合到p300共激活子的C末端结构域，从β2结合位点下游被招募到β2。在小肠中，Cyclin D1仅在增殖活跃的Lieberkuhn隐窝中表达，而在绒毛中不表达。因此，Cyclin D1的抑制可能有助于阻止相对不成熟的上皮祖细胞中发生促胰液素基因的转录。

Expression of the hormone secretin in enteroendocrine cells is restricted to the nondividing villus compartment of the intestine, implying that terminal differentiation is linked to cell cycle arrest and that differentiation is repressed in actively proliferating cells. We have shown previously that the basic helix-loop-helix protein, BETA2/NeuroD, induces cell cycle withdrawal in addition to increasing secretin gene expression. A number of transcription factors important for differentiation are repressed by D cyclins. Repression by D cyclins appears to be independent of its effects on the cell cycle. We show that cyclin D1 represses BETA2/NeuroD-dependent transcription of the secretin gene. Examination of cyclin box mutants shows that repression is unrelated to Cdk4 activation. Although cyclin D1 and BETA2 associate in vivo, they do not directly interact. Cyclin D1 may be recruited to BETA2 by binding to the C-terminal domain of the p300 coactivator, downstream from the BETA2-binding site. In the small intestine, cyclin D1 expression occurs only in the actively proliferating crypts of Lieberkuhn but not in villi. Thus repression by cyclin D1 may serve to prevent secretin gene transcription from occurring in relatively immature epithelial progenitor cells.