Crosstalk between androgen receptor and epidermal growth factor receptor-signalling pathways:: a molecular switch for epithelial cell differentiation
Crosstalk between androgen receptor and epidermal growth factor receptor-signalling pathways:: a molecular switch for epithelial cell differentiation
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DOI：
10.1677/jme-07-0021
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发表时间：
2007-07-01
影响因子：
3.5
通讯作者：
Beaudoin, Claude
中科院分区：
文献类型：
--
作者：
Leotoing, Laurent;Manin, Michele;Beaudoin, Claude
在男性中，雄激素通过雄激素受体(AR)的配体激活促进有性生殖器官的生长和分化。在这里，我们表明雄激素不是与分化过程相关的细胞周期停滞的主要因素，并且当上皮细胞分化时，表皮生长因子(EGF)介导的信号转导干扰AR活性以调节雄激素反应。AR的高表达和雄激素反应性的增强与分化过程中磷酸化ERK1/2的减少相关。这些修饰与细胞在G(0)/G(1)期的募集、p27(Cip1)的上调、p21(Cip1)和p53蛋白的下调以及低磷酸化的Rb的积累有关。暴露于EGF会降低AR的表达水平，并阻断分化细胞中雄激素依赖的转录。当p27(Kip1)蛋白水平降低时，它还可以恢复p53和p21(Cip1)水平，Rb过度磷酸化，ERK1/2激活，并促进细胞周期重新进入。用MEK抑制剂处理可逆转EGF介导的AR在分化细胞中的下调，从而表明EGF与非肿瘤上皮中雄激素信号转导之间存在负相关。有趣的是，当雄激素信号被设置在分化的细胞中时，双氢睾酮对ERK活性产生抑制作用，但矛盾的是，并不改变EGFR(ErbB1)的磷酸化，这表明雄激素能够破坏EGFR-ERK级联反应。总体而言，我们的数据表明，AR和丝裂原激活的蛋白激酶活性之间存在平衡，这有利于维持分化条件或增强细胞的增殖能力。
In the male, androgens promote growth and differentiation of sex reproductive organs through ligand activation of the androgen receptor (AR). Here, we show that androgens are not major actors of the cell cycle arrest associated with the differentiation process, and that the epidermal growth factor (EGF)-mediated signalling interferes with AR activities to regulate androgen response when epithelial cells are differentiated. Higher AR expression and enhanced androgen responsiveness correlate with reduction of phosphorylated ERK1/2 over differentiation. These modifications are associated with recruitment of cells in phase G(0)/G(1), up-regulation of p27(cip1), down-regulation of p21(cip1) and p53 proteins, and accumulation of hypo-phosphorylated Rb. Exposure to EGF reduces AR expression levels and blocks androgen-dependent transcription in differentiated cells. It also restores p53 and p21(cip1) levels, Rb hyper-phosphorylation, ERK1/2 activation and promotes cell cycle re-entry as p27(kiP1) protein levels are decreased. Treatment with a MEK inhibitor reverses the EGF-mediated AR down-regulation in differentiated cells, thus suggesting the existence of an inverse correlation between EGF and androgen signalling in non-tumoural epithelia. Interestingly, when androgen signalling is set in differentiated cells, dihydrotestosterone exerts an inhibitory effect on ERK activity but paradoxically does not modify EGFR (ErbB1) phosphorylation, indicating that androgens are able to disrupt the EGFR-ERK cascade. Overall, our data demonstrate the existence of a balance between AR and mitogen-activated protein kinase activities that favours either the maintenance of differentiated conditions or the enhancement of cell proliferation capacities.