The nucleocytoplasmic shuttling of E2F4 is involved in the regulation of human intestinal epithelial cell proliferation and differentiation
The nucleocytoplasmic shuttling of E2F4 is involved in the regulation of human intestinal epithelial cell proliferation and differentiation
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DOI：
10.1002/jcp.10455
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发表时间：
2004-05-01
影响因子：
5.6
通讯作者：
Rivard, N
中科院分区：
文献类型：
--
作者：
Deschênes, C;Alvarez, L;Rivard, N
控制人肠上皮细胞（HIEC）从增殖到终末分化转变的具体机制在很大程度上仍不清楚。在此，我们分析了 Rb 和 E2F 蛋白在成熟的正常肠上皮细胞模型中的表达和定位，该模型允许在体外以及完整的上皮和结肠癌细胞中重新制定隐窝绒毛轴。我们报告说：（1）在与肠细胞血清剥夺、汇合和终末分化相关的 Go 阻滞期间，E2F1 的表达下调，而 E2F4 蛋白被隔离在细胞质中； (2) 同时，口袋蛋白的低磷酸化形式在细胞核中积累，同时 E2F4 与 pRb 和 p130 的关联增加； (3)人胎肠中高表达核E2F4的细胞Ki67染色均呈阳性； (4)生长因子对HIEC隐窝细胞的激活导致E2F4的核定位增加，这可能归因于该转录因子的丝氨酸/苏氨酸磷酸化的减少； (5)用α/β抑制剂SB203580抑制p38 MAP激酶诱导E2F4转位至细胞核及其转录活性。总之，我们的数据表明 E2F4 在人肠隐窝细胞增殖中发挥关键作用，其细胞质保留以及 Rb 蛋白的隔离可能代表启动细胞周期退出的关键步骤。 J.细胞。生理学。 199: 262-273, 2004。(C) 2003 Wiley-Liss, Inc.
The specific mechanisms controlling the transition from proliferation to terminal differentiation in human intestinal epithelial cells (HIEC) remain largely undefined. Herein, we analyzed the expression and localization of Rb and E2F proteins in well established normal intestinal epithelial cell models which allow for the reenactment of the crypt-villus axis in vitro as well as in intact epithelium and in colon cancer cells. We report that (1) expression of E2F1 is down-regulated while E2F4 protein is sequestered in the cytoplasm during Go arrest associated with serum deprivation, confluency, and terminal differentiation of intestinal cells; (2) concurrently, there is an accumulation of the hypophosphorylated form of the pocket proteins into the nucleus with an increased association of E2F4 with pRb and p130; (3) cells which expressed high levels of nuclear E2F4 are all positive for Ki67 staining in human fetal intestine; (4) activation of HIEC crypt cells by growth factors leads to an increase in the nuclear localization of E2F4 which may be attributable to a decrease in the serine/threonine phosphorylation of this transcription factor; (5) inhibition of p38 MAP kinase with alpha/beta inhibitor SB203580 induces E2F4 translocation into the nucleus and its transcriptional activity. In conclusion, our data suggest a key role for E2F4 in proliferation of human intestinal crypt cells and that its cytoplasmic retention as well as its sequestration by Rb proteins may represent a critical step in initiating cell-cycle exit. J. Cell. Physiol. 199: 262-273, 2004. (C) 2003 Wiley-Liss, Inc.