BMP2 and BMP6 control p57Kip2 expression and cell growth arrest/terminal differentiation in normal primary human epidermal keratinocytes
BMP2 and BMP6 control p57Kip2 expression and cell growth arrest/terminal differentiation in normal primary human epidermal keratinocytes
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DOI：
10.1016/j.cellsig.2006.09.006
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发表时间：
2007-04-01
影响因子：
4.8
通讯作者：
Ehrhart, Jean-Claude
中科院分区：
文献类型：
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作者：
Gosselet, Fablen P.;Magnaldo, Thierry;Ehrhart, Jean-Claude
人表皮角质形成细胞中经典骨形态发生蛋白 (BMP) 信号通路的功能研究仅限于永生化和 p53 突变的 HaCaT 细胞，并且主要依赖于小鼠表皮角质形成细胞中的 BMP6 处理。尽管进行了这些富有洞察力的分析，但 BNIP 信号传导在角质形成细胞的生长停滞和终末分化之间的精确平衡中的作用的分子机制仍然不清楚。目前的研究首先通过使用三种独立的原代滤泡间表皮角质形成细胞株，研究了正常人角质形成细胞中迄今为止未表征的 BMP 信号传导状态和功能。然后我们提供的数据证明了 BMP2 与 BMP6 相比在抑制这些细胞的生长和诱导随后的终末分化方面的作用。第二个相关发现是基于对未处理和 BMP2/6 处理且不存在 EGF 的培养物中存在的集落类型进行克隆分析。 BMP 处理导致克隆从增殖集落转变为流产集落，这表明 BMP 信号传导最有可能抑制干细胞增殖并触发转运扩增细胞的细胞周期退出。第三，我们证明，在细胞周期蛋白依赖性激酶抑制剂的 Cip/Kip 家族的三个成员中，只有 p57(Kip2) 和 p21(Cip1) 具有 BMP2/6 诱导的表达。抑制细胞增殖的一种机制涉及 p57(Kip2) 作为立即的早期反应，这与 p21(Cip1) 不同，p21(Cip1) 的作用很大程度上依赖于从头合成蛋白质。总之，这些结果阐明了正常原代人角质形成细胞中的 BMP 信号传导状态，并支持抑制滤泡间表皮角质形成细胞增殖并在添加 BMP2 或 BMP6 后诱导其终末分化的新机制。 (c) 2006 Elsevier Inc. 保留所有权利。
Functional studies of the canonical Bone Morphogenetic Protein (BMP) signalling pathway in human epidermal keratinocytes have been limited to the immortalized and p53-mutated HaCaT cells and are primarily dependent on BMP6 treatment in mouse epidermal keratinocytes. Despite these insightful analyses, the molecular mechanism underlying the role of BNIP signalling in the precise balance between growth arrest and terminal differentiation of keratinocytes still remains not clearly defined. The current study first investigated the hitherto uncharacterized status and functions of BMP signalling in normal human keratinocytes by using three independent strains of primary interfollicular epidermal keratinocytes. Then we provided data demonstrating the role of BMP2 compared to BMP6 in the inhibition of growth and induction of subsequent terminal differentiation of these cells. A second relevant finding is based on the clonal analysis of colony types present in untreated and BMP2/6-treated cultures in absence of EGF. BMP treatment results in the clonal transition from proliferative to abortive colonies, suggesting that BMP signalling most likely inhibits stem cell proliferation and triggers cell cycle exit from transit amplifying cells. Third, we showed evidence that, of the three members of the Cip/Kip family of cyclin-dependent kinase inhibitors, only p57(Kip2) and p21(Cip1) have a BMP2/6-induced expression. One mechanism of inhibition of cell proliferation involves p57(Kip2) as an immediate early response, in contradistinction with p21(Cip1) which largely depends on de novo protein synthesis for its effect to proceed. All together, these results clarify the BMP signalling status in normal primary human keratinocytes and support a new mechanism of inhibition of the proliferation of interfollicular epidermal keratinocytes coupled with induction of their terminal differentiation following BMP2 or BMP6 addition. (c) 2006 Elsevier Inc. All rights reserved.