c-Met expression is regulated by Mitf in the melanocyte lineage
c-Met expression is regulated by Mitf in the melanocyte lineage
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DOI：
10.1074/jbc.m513094200
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发表时间：
2006-04-14
影响因子：
4.8
通讯作者：
Fisher, DE
中科院分区：
文献类型：
--
作者：
McGill, GG;Haq, R;Fisher, DE
肝细胞生长因子（HGF）/c-Met信号被认为是黑素细胞发育和黑色素瘤转移的关键途径。在此，观察到HGF刺激黑素细胞上调c-Met表达。在努力破译HGF上调其受体的机制中，我们发现c-Met是Mitf的直接转录靶点。这与人c-Met启动子的染色质免疫沉淀实验以及腺病毒表达的Mitf调节黑素细胞中内源性c-Met蛋白水平的能力证实。Mitf的破坏阻断了内源性c-Met信息和蛋白水平的HGF依赖性增加，表明HGF通过Mitf调节其自身的受体水平。最后，Mitf的显性负抑制导致黑素细胞和黑色素瘤细胞对HGF依赖性基质侵袭的深刻抵抗，表明该途径在黑素细胞发育和黑色素瘤中的生理作用。
Hepatocyte growth factor (HGF)/c-Met signaling is thought to be a key pathway in both melanocyte development and melanoma metastasis. Here, HGF stimulation of melanocytes was seen to upregulate c-Met expression. In an effort to decipher the mechanism by which HGF up-regulates its receptor, we found that c-Met is a direct transcriptional target of Mitf. This was confirmed with chromatin immunoprecipitation experiments of the human c-Met promoter, as well as by the ability of adenovirally expressed Mitf to modulate endogenous c-Met protein levels in melanocytes. Disruption of Mitf blocked HGF-dependent increases in endogenous c-Met message and protein levels, indicating that HGF regulates its own receptor levels via Mitf. Finally, dominant-negative inhibition of Mitf resulted in profound resistance of melanocytes and melanoma cells to HGF-dependent matrix invasion, suggesting a physiologic role for this pathway in melanocytic development and melanoma.