The estrogen-dependent c-JunER protein causes a reversible loss of mammary epithelial cell polarity involving a destabilization of adherens junctions.
The estrogen-dependent c-JunER protein causes a reversible loss of mammary epithelial cell polarity involving a destabilization of adherens junctions.
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DOI：
10.1083/jcb.132.6.1115
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发表时间：
1996-03
期刊：
影响因子：
--
通讯作者：
Beug H
中科院分区：
文献类型：
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作者：
Fialka I;Schwarz H;Reichmann E;Oft M;Busslinger M;Beug H
已知表皮生长因子（EGF）受体家族成员特异性参与乳腺癌的发生。作为激活受体的核靶点，我们研究了乳腺上皮细胞中的c-Jun。为此，我们使用了由雌激素严格控制的c-JunER融合蛋白。激素激活JunER导致多种AP-1靶基因的转录调节。激素激活的JunER诱导上皮极性的丧失，细胞间连接和正常屏障功能的破坏以及不规则多层的形成。这些变化在激素戒断后是完全可逆的。上皮极性的丧失涉及顶端和基底侧蛋白质重新分布到整个质膜。E-钙粘蛋白和β-连环蛋白的重新分布伴随着这两种蛋白质之间形成的复合物的不稳定，导致β-连环蛋白在洗涤剂可溶性级分中富集。未诱导的细胞能够在胶原蛋白I凝胶中形成三维管状结构，其在JunER活化后被破坏，导致不规则的细胞聚集体。JunER诱导的管状结构破坏依赖于生长因子的主动信号传导。此外，通过加入酸性成纤维细胞生长因子（aFGF），可以在正常细胞中模拟JunER的作用。这些数据表明，c-Jun在上皮细胞中的一个可能的功能是调节上皮极性和调节组织结构，这些过程对于正常乳腺发育和癌变的起始步骤可能同样重要。
Members of the epidermal growth factor (EGF) receptor family are known to be specifically involved in mammary carcinogenesis. As a nuclear target of activated receptors, we examined c-Jun in mammary epithelial cells. For this, we used a c-JunER fusion protein which was tightly controlled by estrogen. Activation of the JunER by hormone resulted in the transcriptional regulation of a variety of AP-1 target genes. Hormone-activated JunER induced the loss of epithelial polarity, a disruption of intercellular junctions and normal barrier function and the formation of irregular multilayers. These changes were completely reversible upon hormone withdrawal. Loss of epithelial polarity involved redistribution of both apical and basolateral proteins to the entire plasma membrane. The redistribution of E-cadherin and beta- catenin was accompanied by a destabilization of complexes formed between these two proteins, leading to an enrichment of beta-catenin in the detergent-soluble fraction. Uninduced cells were able to form three- dimensional tubular structures in collagen I gels which were disrupted upon JunER activation, leading to irregular cell aggregates. The JunER- induced disruption of tubular structures was dependent on active signaling by growth factors. Moreover, the effects of JunER could be mimicked in normal cells by the addition of acidic fibroblast growth factor (aFGF). These data suggest that a possible function of c-Jun in epithelial cells is to modulate epithelial polarity and regulate tissue organization, processes which may be equally important for both normal breast development and as initiating steps in carcinogenesis.