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

肠内分泌细胞中激素分泌素的表达仅限于肠未分裂的绒毛隔室，这意味着终末分化与细胞周期阻滞有关，而在积极增殖的细胞中分化受到抑制。我们之前已经证明，基本的螺旋-环-螺旋蛋白BETA2/NeuroD除了增加分泌素基因表达外，还会诱导细胞周期退出。许多对分化很重要的转录因子受到D细胞周期蛋白的抑制。D细胞周期蛋白的抑制作用似乎与它对细胞周期的影响无关。我们发现cyclin D1抑制分泌素基因的BETA2/ neurod依赖性转录。对细胞周期蛋白盒子突变体的检测表明，抑制与Cdk4激活无关。尽管cyclin D1和BETA2在体内相互关联，但它们并不直接相互作用。Cyclin D1可能通过结合p300共激活子的c端结构域（位于BETA2结合位点的下游）被募集到BETA2。在小肠中，cyclin D1只在活跃增殖的Lieberkuhn隐窝中表达，而在绒毛中不表达。因此，细胞周期蛋白D1的抑制可能有助于阻止分泌素基因转录在相对不成熟的上皮祖细胞中发生。

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.