PAX3 and ETS1 synergistically activate MET expression in melanoma cells.
PAX3 and ETS1 synergistically activate MET expression in melanoma cells.
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作者：
黑色素瘤是一种高度侵袭性的疾病，由于肿瘤生长快速、细胞凋亡抵抗和高转移潜力而难以治疗。 MET 酪氨酸激酶受体促进许多这些细胞过程，虽然 MET 在黑色素瘤中经常过度表达，但驱动这种过度表达的机制尚不清楚。由于 MET 基因在黑色素瘤中很少发生突变或扩增，因此 MET 过表达可能是通过启动子元件增加激活来驱动的。在本报告中，我们发现转录因子 PAX3 和 ETS1 直接相互作用，协同激活 MET 表达。抑制黑色素瘤细胞中 PAX3 和 ETS1 的表达会导致 MET 受体水平显着降低。 300 bp 5' 近端 MET 启动子包含一个 PAX3 响应元件和两个 ETS1 共有基序。虽然 ETS1 可以在没有辅因子的情况下适度激活这两个位点，但第一个位点的强 MET 启动子激活是 PAX 依赖性的，并且需要 PAX3 的存在，而第二个位点则不依赖于 PAX。 HGF 依赖性 ETS1 激活增强了 ETS1 通过第二个位点对 MET 的诱导，从而 MET 间接促进其自身表达。我们进一步发现显性失活 ETS1 的表达降低了黑色素瘤细胞在培养物和体内生长的能力。因此，我们发现ETS1通过PAX依赖性和独立机制表达MET来促进黑色素瘤发展。
Melanoma is a highly aggressive disease that is difficult to treat due to rapid tumor growth, apoptotic resistance, and high metastatic potential. The MET tyrosine kinase receptor promotes many of these cellular processes, and while MET is often overexpressed in melanoma, the mechanism driving this overexpression is unknown. Since the MET gene is rarely mutated or amplified in melanoma, MET overexpression may be driven by to increased activation through promoter elements. In this report, we find that transcription factors PAX3 and ETS1 directly interact to synergistically activate MET expression. Inhibition of PAX3 and ETS1 expression in melanoma cells leads to a significant reduction of MET receptor levels. The 300 bp 5′ proximal MET promoter contains a PAX3 response element and two ETS1 consensus motifs. While ETS1 can moderately activate both of these sites without cofactors, robust MET promoter activation of the first site is PAX-dependent and requires the presence of PAX3, while the second site is PAX-independent. The induction of MET by ETS1 via this second site is enhanced by HGF-dependent ETS1 activation, thereby MET indirectly promotes its own expression. We further find that expression of a dominant negative ETS1 reduces the ability of melanoma cells to grow both in culture and in vivo. Thus, we discover a pathway where ETS1 advances melanoma through the expression of MET via PAX-dependent and independent mechanisms.
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影响因子：
3.7
作者：
Medic S;Ziman M
通讯作者：
Ziman M
DOI：
10.1073/pnas.93.9.4213
发表时间：
1996-04-30
影响因子：
11.1
作者：
Epstein, JA;Shapiro, DN;Maas, RL
通讯作者：
Maas, RL
影响因子：
4.8
作者：
Beuret, Laurent;Flori, Enrica;Ballotti, Robert
通讯作者：
Ballotti, Robert
DOI：
10.1006/bbrc.2001.5521
发表时间：
2001-09-07
影响因子：
3.1
作者：
Jiang, Y;Xu, WX;Yang, XM
通讯作者：
Yang, XM
影响因子：
5.6
作者：
Fitzsimmons, Daniel;Lukin, Kara;Hagman, James
通讯作者：
Hagman, James