A Notch1-neuregulin1 autocrine signaling loop contributes to melanoma growth.
A Notch1-neuregulin1 autocrine signaling loop contributes to melanoma growth.
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DOI：
10.1038/onc.2011.606
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发表时间：
2012-10-25
期刊：
影响因子：
8
通讯作者：
Bedogni B
中科院分区：
文献类型：
--
作者：
Zhang K;Wong P;Zhang L;Jacobs B;Borden EC;Aster JC;Bedogni B
Notch 通路是一种进化保守的信号级联，在成黑细胞和黑素细胞干细胞稳态中具有重要作用。 Notch信号正在成为黑色素瘤（最致命的皮肤癌）的关键参与者。在黑色素瘤中，Notch1 被不当重新激活并导致黑色素瘤致瘤性。在这里，我们提出了一种Notch1促进该疾病的新机制。我们发现Notch1通过与其启动子区域结合直接调节神经调节蛋白1（NRG1）的转录。 NRG1 是 ERBB3 和 4 的配体，ERBB3 和 4 是表皮生长因子受体家族的成员，参与多种癌症的发生和进展。 Notch1 和 NRG1 表达与黑色素瘤相关，抑制 NRG1 信号传导会导致黑色素瘤细胞生长抑制和肿瘤生长延迟。从机制上讲，这些效应与 PI3Kinase/Akt 信号通路的抑制以及 p27Kip1 的积累有关。另一方面，添加重组NRG1可以部分恢复因Notch1消融而抑制的黑色素瘤细胞生长。总而言之，我们的研究结果强调了 Notch1 和 NRG1 之间一个新的、以前未描述的自分泌信号环路，它控制黑色素瘤的生长，并提供了实验证据，表明 Notch 和 ERBB 信号传导的靶向可能代表黑色素瘤的一种新的潜在治疗方法
The Notch pathway is an evolutionary conserved signaling cascade that has an essential role in melanoblast and melanocyte stem cell homeostasis. Notch signaling is emerging as a key player in melanoma, the most deadly form of skin cancer. In melanoma, Notch1 is inappropriately reactivated and contributes to melanoma tumorigenicity. Here, we propose a novel mechanism by which Notch1 promotes the disease. We found that Notch1 directly regulates the transcription of neuregulin1 (NRG1) by binding to its promoter region. NRG1 is the ligand for ERBB3 and 4, members of the Epidermal Growth Factor family of receptors that are involved in the genesis and progression of a number of cancers. Notch1 and NRG1 expression are associated in melanoma and inhibition of NRG1 signaling leads to melanoma cell growth inhibition and tumor growth delay. Mechanistically, these effects are associated with the inhibition of the PI3Kinase/Akt signaling pathway and with the accumulation of p27Kip1. On the other end, addition of recombinant NRG1 can partially restore melanoma cell growth that is inhibited by Notch1 ablation. Taken together, our findings underline a new, previously undescribed autocrine signaling loop between Notch1 and NRG1 that controls melanoma growth and provide experimental evidence that the targeting of Notch and ERBB signaling may represent a novel potential therapeutic approach in melanoma
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DOI：
10.1111/j.1600-0749.2006.00322.x
发表时间：
2006-08-01
期刊：
PIGMENT CELL RESEARCH
影响因子：
--
作者：
Hoek, Keith S.;Schlegel, Natalie C.;Dummer, Reinhard
通讯作者：
Dummer, Reinhard
影响因子：
11.5
作者：
Magnifico, Alessandra;Albano, Luisa;Tagliabue, Elda
通讯作者：
Tagliabue, Elda
DOI：
10.1111/j.1600-0749.2007.00375.x
发表时间：
2007-06-01
期刊：
PIGMENT CELL RESEARCH
影响因子：
--
作者：
Johansson, Peter;Pavey, Sandra;Hayward, Nicholas
通讯作者：
Hayward, Nicholas
影响因子：
5
作者：
Fukazawa, R;Miller, TA;Sawyer, DB
通讯作者：
Sawyer, DB
影响因子：
11.2
作者：
Liu, ZJ;Xiao, M;Herlyn, M
通讯作者：
Herlyn, M