Abstract:
Mahogunin Ring Finger 1 is an E3-ubiquitin ligase encoded by the color gene MGRN1. Our previous in vitro and in vivo studies demonstrated that Mgrn1 deletion in mouse melanoma cells induced cell differentiation and adhesion, and decreased cell motility and invasion on collagen I, and lung colonization in an in vivo model. Here, we investigated the role of MGRN1 on human melanoma cell morphology, adhesion and expression of genes/proteins involved in an EMT-like transition. We demonstrated that wild-type BRAF human melanoma cells adopted a clustering-like morphology on collagen I, with permanent MGRN1 abrogation resulting in bigger cell clusters. Enhanced intercellular adhesion was mostly mediated by induction of E-cadherin and higher co-localization with β-catenin. Transcriptional upregulation of E-cadherin likely occurred through downregulation of the ZEB1 repressor. Finally, pulldown assays showed reduced activation of CDC42 in the absence of MGRN1, which was reverted after E-cadherin silencing. Overall, these findings highlight a new MGRN1-dependent pathway regulating melanoma cell shape, motility, and invasion potential.
摘要:
桃花素环指1是由颜色基因MGRN1编码的E3-泛素连接酶。我们先前的体外和体内研究表明,小鼠黑色素瘤细胞中Mgrn1缺失诱导细胞分化和粘附,减少了细胞运动和对I型胶原的侵袭,和体内模型中的肺定植。这里,我们研究了MGRN1对人黑色素瘤细胞形态的作用,参与EMT样转变的基因/蛋白质的粘附和表达。我们证明了野生型BRAF人黑色素瘤细胞在胶原蛋白I上采用了聚类样形态,永久的MGRN1废除导致更大的细胞簇。增强的细胞间粘附主要是由E-cadherin的诱导和与β-catenin的更高的共定位介导的。E-钙粘蛋白的转录上调可能是通过下调ZEB1阻遏物而发生的。最后,下拉测定显示在缺乏MGRN1的情况下CDC42的活化降低,其在E-钙黏着蛋白沉默后恢复。总的来说,这些发现突出了一个新的MGRN1依赖性途径调节黑色素瘤细胞的形状,运动性,和入侵潜力。