MELK Promotes Melanoma Growth by Stimulating the NF-κB Pathway.
MELK Promotes Melanoma Growth by Stimulating the NF-κB Pathway.
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DOI：
10.1016/j.celrep.2017.11.033
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发表时间：
2017-12-05
期刊：
影响因子：
8.8
通讯作者：
Wajapeyee N
中科院分区：
文献类型：
--
作者：
Janostiak R;Rauniyar N;Lam TT;Ou J;Zhu LJ;Green MR;Wajapeyee N
黑色素瘤占皮肤癌相关死亡的80%以上，目前的治疗方法只能为患者提供短期好处。在这里，我们展示了在黑色素瘤细胞中，母体胚胎亮氨酸拉链激酶(Melk)通过转录因子E2F1被MAP激酶途径转录上调。Melk基因敲除或药物抑制可阻断黑色素瘤的生长，并增强BRAFV600E抑制剂对黑色素瘤细胞的抑制作用。为了确定Melk功能的介体，我们进行了细胞培养中氨基酸的稳定同位素标记(SILAC)，并鉴定了Melk抑制后磷酸化下调的469个蛋白质。值得注意的是，这些蛋白中有139个是BRAF或MEK的底物，表明Melk是MAPK途径的重要下游介体。此外，我们还发现Melk通过序列小体1(Sqstm1/p62)激活了NF-κB通路的活性，从而促进了黑色素瘤的生长。总而言之，这些结果支持了Melk在黑色素瘤生长中的重要作用，MAPK途径的下游。Janostiak等人。发现Melk在黑色素瘤中过度表达，是黑色素瘤生长所必需的。Melk通过Sqstm1调节NF-κB途径，这在一定程度上是其促进黑色素瘤生长所必需的。
Melanoma accounts for over 80% of skin cancer-related deaths and current therapies provide only short-term benefit to patients. Here, we show in melanoma cells that maternal embryonic leucine zipper kinase (MELK) is transcriptionally upregulated by the MAP kinase pathway via transcription factor E2F1. MELK knockdown or pharmacological inhibition blocked melanoma growth and enhanced the effectiveness of BRAFV600E inhibitor against melanoma cells. To identify mediators of MELK function, we performed stable isotope labeling with amino acids in cell culture (SILAC) and identified 469 proteins that had downregulated phosphorylation after MELK inhibition. Remarkably, 139 of these proteins were previously reported as substrates of BRAF or MEK, demonstrating that MELK is an important downstream mediator of the MAPK pathway. Furthermore, we show that MELK promotes melanoma growth by activating NF-κB pathway activity via Sequestosome 1 (SQSTM1/p62). Collectively, these results underpin an important role for MELK in melanoma growth, downstream of the MAPK pathway. Janostiak et al. find that MELK is overexpressed in melanoma and is necessary for melanoma growth. MELK regulates NF-κB pathway via SQSTM1, which in part is necessary for its ability to promote melanoma growth.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
7.4
作者：
Madonna G;Ullman CD;Gentilcore G;Palmieri G;Ascierto PA
通讯作者：
Ascierto PA
影响因子：
4.8
作者：
Dhawan, P;Richmond, A
通讯作者：
Richmond, A
影响因子：
50.3
作者：
Duran, Angeles;Linares, Juan F.;Moscat, Jorge
通讯作者：
Moscat, Jorge
影响因子：
1.9
作者：
Erstad, Derek J.;Cusack, James C., Jr.
通讯作者：
Cusack, James C., Jr.