Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma.
Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma.
复制标题
DOI：
10.1016/j.ccr.2013.05.005
复制
发表时间：
2013-07-08
期刊：
影响因子：
50.3
通讯作者：
Eilers M
中科院分区：
文献类型：
--
作者：
Brockmann M;Poon E;Berry T;Carstensen A;Deubzer HE;Rycak L;Jamin Y;Thway K;Robinson SP;Roels F;Witt O;Fischer M;Chesler L;Eilers M
MYCN扩增是包括神经母细胞瘤在内的人类神经内分泌肿瘤亚群中的驱动突变。没有靶向N-Myc（MYCN编码的蛋白质）的小分子在临床上可用。N-Myc与Aurora-A激酶形成复合物，其保护N-Myc免受蛋白酶体降解。虽然N-Myc的稳定性不需要Aurora-A的催化活性，但我们在此表明，两种Aurora-A抑制剂MLN 8054和MLN 8237破坏了Aurora-A/N-Myc复合物，并促进了Fbxw 7泛素连接酶介导的N-Myc降解。Aurora-A/N-Myc复合物的破坏抑制N-Myc依赖性转录，与MYCN驱动的神经母细胞瘤小鼠模型中的肿瘤消退和延长的存活相关。我们得出结论，Aurora-A是一个可访问的目标，使N-Myc的不稳定成为一个可行的治疗策略。
Amplification of MYCN is a driver mutation in a subset of human neuroendocrine tumors including neuroblastoma. No small molecules that target N-Myc, the protein encoded by MYCN, are clinically available. N-Myc forms a complex with the Aurora-A kinase, which protects N-Myc from proteasomal degradation. Although stabilization of N-Myc does not require the catalytic activity of Aurora-A, we show here that two Aurora-A inhibitors, MLN8054 and MLN8237, disrupt the Aurora-A/N-Myc complex and promote degradation of N-Myc mediated by the Fbxw7 ubiquitin ligase. Disruption of the Aurora-A/N-Myc complex inhibits N-Myc-dependent transcription, correlating with tumor regression and prolonged survival in a mouse model of MYCN-driven neuroblastoma. We conclude that Aurora-A is an accessible target that makes destabilization of N-Myc a viable therapeutic strategy.
登录
查看更多内容
影响因子：
5.3
作者：
de Marval, PLM;Macias, E;Rodriguez-Puebla, ML
通讯作者：
Rodriguez-Puebla, ML
影响因子：
10.5
作者：
Bouchard, C;Dittrich, O;Lüscher, B
通讯作者：
Lüscher, B
影响因子：
50.3
作者：
Rakhra K;Bachireddy P;Zabuawala T;Zeiser R;Xu L;Kopelman A;Fan AC;Yang Q;Braunstein L;Crosby E;Ryeom S;Felsher DW
通讯作者：
Felsher DW
影响因子：
64.5
作者：
Delmore JE;Issa GC;Lemieux ME;Rahl PB;Shi J;Jacobs HM;Kastritis E;Gilpatrick T;Paranal RM;Qi J;Chesi M;Schinzel AC;McKeown MR;Heffernan TP;Vakoc CR;Bergsagel PL;Ghobrial IM;Richardson PG;Young RA;Hahn WC;Anderson KC;Kung AL;Bradner JE;Mitsiades CS
通讯作者：
Mitsiades CS
影响因子：
4
作者：
Sloane, Dominic A.;Trikic, Michael Z.;Eyers, Patrick A.
通讯作者：
Eyers, Patrick A.