The caudal-related homeodomain protein Cdx1 inhibits proliferation of intestinal epithelial cells by down-regulation of D-type cyclins
The caudal-related homeodomain protein Cdx1 inhibits proliferation of intestinal epithelial cells by down-regulation of D-type cyclins
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DOI：
10.1074/jbc.275.6.4499
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发表时间：
2000-02-11
影响因子：
4.8
通讯作者：
Traber, PG
中科院分区：
文献类型：
--
作者：
Lynch, J;Suh, ER;Traber, PG
Gdx1是调节肠道特异性基因表达的同源结构域转录因子。实验证据表明，Cdx1可能参与细胞周期调节，但其作用尚未明确，机制尚未探索。我们使用可诱导构建物稳定转染和复制缺陷腺病毒短暂表达诱导大鼠IEC6细胞（一种不表达Cdx1蛋白的非转化肠上皮细胞系）表达Cdx1。Cdx1的表达显著降低IEC6细胞的增殖，细胞在细胞周期的G(0)/G(1)期积累。细胞周期阻滞伴随着视网膜母细胞瘤蛋白（pRb）和pRb相关的p130蛋白的低磷酸化形式的增加。多种周期蛋白依赖性激酶抑制剂的蛋白水平要么保持不变（p16, p18, p21， p27和p57），要么未检测到（p15和p19）。最重要的是，细胞周期蛋白D1和D2的水平随着Cdx1的表达而显著降低，但细胞周期蛋白D3， E或G(1)激酶的表达没有显著降低。此外，细胞周期蛋白依赖性激酶4的活性随着细胞周期蛋白D蛋白的降低而降低。我们得出结论，Cdx1通过G(0)/G(1)抑制肠上皮细胞增殖，很可能通过调节细胞周期蛋白D1和D2蛋白水平来调节。
Gdx1 is a homeodomain transcription factor that regulates intestine-specific gene expression. Experimental evidence suggests that Cdx1 may be involved in cell cycle regulation, but its role is ill defined and the mechanisms have not been explored. We used stable transfection of inducible constructs and transient expression with a replication-deficient adenovirus to induce Cdx1 expression in rat IEC6 cells, a non-transformed intestinal epithelial cell line that does not express Cdx1 protein. Expression of Cdx1 markedly reduced proliferation of IEC6 cells with accumulation of cells in the G(0)/G(1) phase of the cell cycle. Cell cycle arrest was accompanied by an increase in the hypophosphorylated forms of the retinoblastoma protein (pRb) and the pRb-related p130 protein. Protein levels of multiple cyclin-dependent kinase inhibitors were either unchanged (p16, p18, p21, p27, and p57) or were not detected (p15 and p19), Most significantly, levels of cyclins D1 and D2 were markedly diminished with Cdx1 expression, but not cyclins D3, E, or the G(1) kinases, Additionally, cyclin-dependent kinase-4 activity was decreased in association with decreased cyclin D protein, We conclude that Cdx1 regulates intestinal epithelial cell proliferation by inhibiting progression through G(0)/G(1), most likely via modulation of cyclin D1 and D2 protein levels.