Proliferation, cell cycle exit, and onset of terminal differentiation in cultured keratinocytes:: Pre-programmed pathways in control of c-Myc and Notch1 prevail over extracellular calcium signals
Proliferation, cell cycle exit, and onset of terminal differentiation in cultured keratinocytes:: Pre-programmed pathways in control of c-Myc and Notch1 prevail over extracellular calcium signals
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DOI：
10.1111/j.0022-202x.2005.23655.x
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发表时间：
2005-05-01
影响因子：
6.5
通讯作者：
Müller, EJ
中科院分区：
文献类型：
--
作者：
Kolly, C;Suter, MM;Müller, EJ
到目前为止，据报道，细胞外钙从低到高的转换诱导培养的人和小鼠角质形成细胞的生长停滞和终末分化。我们观察到犬和小鼠角质形成细胞在高（分别为1.8 mM，1.2 mM）或低（0.09和0.06 mM）含钙培养基中增殖。如本文所述，对这种现象的深入分析表明，当犬和小鼠角质形成细胞达到融合时，增殖和终末分化之间的转换与钙条件无关。“汇合开关”与细胞周期抑制剂p21（WAF 1）和p27（KIP 1）以及标志终末分化开始的蛋白质的转录上调相一致。它还伴随着c-Myc的下调和核清除，以及Notch 1的相反激活，这被证明是该过程的关键决定因素。总之，这项研究表明，即使在缺乏和类似于它们的体内环境，培养的犬和小鼠角质形成细胞遵循预定义的分化程序。该程序控制c-Myc和Notch 1，并且除了细胞-细胞接触所提供的信号外，不需要用于终末分化起始的互补信号。一旦触发，终末分化过程的完成取决于升高的细胞外钙以稳定细胞间连接和皮质包膜的组分。
So far it was reported that a switch from low to high extracellular calcium induces growth arrest and terminal differentiation in cultured human and mouse keratinocytes. We had observed that both canine and mouse keratinocytes proliferate in high (1.8 mM, respectively, 1.2 mM) or low (0.09 and 0.06 mM) calcium-containing medium. In-depth analysis of this phenomenon revealed, as reported here, that the switch between proliferation and terminal differentiation occurred irrespective of calcium conditions when the canine and murine keratinocytes reach confluency. The "confluency switch" coincided with transcriptional upregulation of cell cycle inhibitors p21(WAF1) and p27(KIP1) as well as proteins marking onset of terminal differentiation. It was further accompanied by downregulation and nuclear clearance of c-Myc, and conversely activation of Notch1, which are shown to be critical determinants of this process. Together, this study demonstrates that even in the absence of and similar to their in vivo environment, cultured canine and mouse keratinocytes follow a pre-defined differentiation program. This program is in control of c-Myc and Notch1 and does not require complementary signals for onset of terminal differentiation except those given by cell-cell contact. Once triggered, completion of the terminal differentiation process depends on elevated extracellular calcium to stabilize intercellular junctions and components of the cornified envelope.