Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing.
Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing.
复制标题
DOI：
10.1038/ng.1041
复制
发表时间：
2011-12-25
期刊：
影响因子：
30.8
通讯作者：
Hayward, Nicholas K.
中科院分区：
文献类型：
--
作者：
Stark, Mitchell S.;Woods, Susan L.;Gartside, Michael G.;Bonazzi, Vanessa F.;Dutton-Regester, Ken;Aoude, Lauren G.;Chow, Donald;Sereduk, Chris;Niemi, Natalie M.;Tang, Nanyun;Ellis, Jonathan J.;Reid, Jeffrey;Zismann, Victoria;Tyagi, Sonika;Muzny, Donna;Newsham, Irene;Wu, YuanQing;Palmer, Jane M.;Pollak, Thomas;Youngkin, David;Brooks, Bradford R.;Lanagan, Catherine;Schmidt, Christopher W.;Kobe, Bostjan;MacKeigan, Jeffrey P.;Yin, Hongwei;Brown, Kevin M.;Gibbs, Richard;Trent, Jeffrey;Hayward, Nicholas K.
我们对8个黑色素瘤外显子组进行测序，以鉴定转移性黑色素瘤中新的体细胞突变。聚焦于MAP3K家族，我们发现24%的黑色素瘤细胞系在MAP3K5或MAP3K9的蛋白质编码区发生突变。结构模型预测，激酶结构域的突变可能影响MAP3K5/9蛋白激酶的活性和调控。在85%和67%的黑色素瘤样本中，MAP3K5和MAP3K9的突变位置和杂合性的缺失表明，突变可能是失活的。体外激酶分析显示，MAP3K5 I780F和MAP3K9 W333X突变体的激酶活性降低。HEK293T细胞中MAP3K5或MAP3K9突变体的过表达会降低下游MAP激酶的磷酸化。使用siRNA减弱黑色素瘤细胞中MAP3K9的功能导致替莫唑胺治疗后细胞活力增加，这表明MAP3K途径活性降低可导致黑色素瘤的化疗耐药。
We sequenced 8 melanoma exomes to identify novel somatic mutations in metastatic melanoma. Focusing on the MAP3K family, we found that 24% of melanoma cell lines have mutations in the protein-coding regions of either MAP3K5 or MAP3K9. Structural modelling predicts that mutations in the kinase domain may affect the activity and regulation of MAP3K5/9 protein kinases. The position of the mutations and loss of heterozygosity of MAP3K5 and MAP3K9 in 85% and 67% of melanoma samples, respectively, together suggest that the mutations are likely inactivating. In vitro kinase assay shows reduction in kinase activity in MAP3K5 I780F and MAP3K9 W333X mutants. Overexpression of MAP3K5 or MAP3K9 mutant in HEK293T cells reduces phosphorylation of downstream MAP kinases. Attenuation of MAP3K9 function in melanoma cells using siRNA leads to increased cell viability after temozolomide treatment, suggesting that decreased MAP3K pathway activity can lead to chemoresistance in melanoma.
登录
查看更多内容
宇宙（癌症中的体细胞突变目录）数据库和网站。
影响因子：
8.8
作者：
Bamford, S;Dawson, E;Forbes, S;Clements, J;Pettett, R;Dogan, A;Flanagan, A;Teague, J;Futreal, PA;Stratton, MR;Wooster, R
通讯作者：
Wooster, R
影响因子：
3.9
作者：
Wei, Xiaomu;Moncada-Pazos, Angela;Cal, Santiago;Soria-Valles, Clara;Gartner, Jared;Rudloff, Udo;Lin, Jimmy C.;Rosenberg, Steven A.;Lopez-Otin, Carlos;Samuels, Yardena
通讯作者：
Samuels, Yardena
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
11.2
作者：
Solomon DA;Kim JS;Cronin JC;Sibenaller Z;Ryken T;Rosenberg SA;Ressom H;Jean W;Bigner D;Yan H;Samuels Y;Waldman T
通讯作者：
Waldman T
影响因子：
64.8
作者：
Johannessen, Cory M.;Boehm, Jesse S.;Kim, So Young;Thomas, Sapana R.;Wardwell, Leslie;Johnson, Laura A.;Emery, Caroline M.;Stransky, Nicolas;Cogdill, Alexandria P.;Barretina, Jordi;Caponigro, Giordano;Hieronymus, Haley;Murray, Ryan R.;Salehi-Ashtiani, Kourosh;Hill, David E.;Vidal, Marc;Zhao, Jean J.;Yang, Xiaoping;Alkan, Ozan;Kim, Sungjoon;Harris, Jennifer L.;Wilson, Christopher J.;Myer, Vic E.;Finan, Peter M.;Root, David E.;Roberts, Thomas M.;Golub, Todd;Flaherty, Keith T.;Dummer, Reinhard;Weber, Barbara L.;Sellers, William R.;Schlegel, Robert;Wargo, Jennifer A.;Hahn, William C.;Garraway, Levi A.
通讯作者：
Garraway, Levi A.