Up-regulation of MET expression by α-melanocyte-stimulating hormone and MITF allows hepatocyte growth factor to protect melanocytes and melanoma cells from apoptosis
Up-regulation of MET expression by α-melanocyte-stimulating hormone and MITF allows hepatocyte growth factor to protect melanocytes and melanoma cells from apoptosis
复制标题
DOI：
10.1074/jbc.m611563200
复制
发表时间：
2007-05-11
影响因子：
4.8
通讯作者：
Ballotti, Robert
中科院分区：
文献类型：
--
作者：
Beuret, Laurent;Flori, Enrica;Ballotti, Robert
MET原癌基因编码肝细胞生长因子（HGF）受体，一种参与黑素细胞生长和黑色素瘤发展的质膜酪氨酸激酶。在小鼠黑色素瘤细胞中，α MSH通过激活cAMP途径增加Met表达。然而，cAMP调节MET的机制和这种增加的生物学后果尚不清楚。在本报告中，我们表明，α MSH调节MET表达在人类黑素细胞和小鼠黑色素瘤细胞通过转录机制，需要MITF。此外，腺病毒驱动的MITF表达足以增加黑素瘤细胞中的MET。MET启动子的功能分析使我们能够鉴定在人和小鼠启动子中保守的介导MITF作用的E-box基序。有趣的是，cAMP上调MET表达导致HGF信号传导加剧，并允许HGF保护黑素细胞和黑素瘤细胞免于凋亡。因此，诱导MITF表达的生理刺激或病理事件可能导致MET表达增加，从而有利于黑素瘤存活。这些观察结果加强了MITF和MET在黑色素瘤发展中的作用。
The MET proto-oncogene encodes for the hepatocyte growth factor (HGF) receptor, a plasma membrane tyrosine kinase that is involved in melanocyte growth and melanoma development. In mouse melanoma cells, Met expression is increased by alpha MSH via the activation of the cAMP pathway. However, the mechanism by which cAMP regulates MET and the biological consequences of this increase were not known. In the present report, we show that alpha MSH regulates MET expression in both human melanocytes and mouse melanoma cells through a transcriptional mechanism that requires MITF. Furthermore, the adenovirus driven expression of MITF is sufficient to increase MET in melanoma cells. Functional analysis of the MET promoter allows us to identify an E-box motif conserved in both human and mouse promoter that mediates the effect of MITF. Interestingly, up-regulation of MET expression by cAMP leads to an exacerbated HGF signaling and allows HGF to protect melanocytes and melanoma cells from apoptosis. Thus, physiological stimuli or pathological events that would induce MITF expression may lead to increased MET expression thereby favoring melanoma survival. These observations strengthen the roles of MITF and MET in melanoma development.