Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma.
Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma.
复制标题
突变特异性RAS致癌性解释了NRAS密码子61在黑色素瘤中的选择。
DOI：
10.1158/2159-8290.cd-14-0729
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发表时间：
2014-12
期刊：
影响因子：
28.2
通讯作者：
Sharpless NE
中科院分区：
文献类型：
--
作者：
Burd CE;Liu W;Huynh MV;Waqas MA;Gillahan JE;Clark KS;Fu K;Martin BL;Jeck WR;Souroullas GP;Darr DB;Zedek DC;Miley MJ;Baguley BC;Campbell SL;Sharpless NE
N-RAS mutation at codon 12, 13 or 61 is associated with transformation; yet, in melanoma, such alterations are nearly exclusive to codon 61. Here, we compared the melanoma susceptibility of an N-RasQ61R knock-in allele to similarly designed K-RasG12D and N-RasG12D alleles. With concomitant p16INK4a inactivation, K-RasG12D or N-RasQ61R expression efficiently promoted melanoma in vivo, whereas N-RasG12D did not. Additionally, N-RasQ61R mutation potently cooperated with Lkb1/Stk11 loss to induce highly metastatic disease. Functional comparisons of N-RasQ61R and N-RasG12D revealed little difference in the ability of these proteins to engage PI3K or RAF. Instead, N-RasQ61R showed enhanced nucleotide binding, decreased intrinsic GTPase activity and increased stability when compared to N-RasG12D. This work identifies a faithful model of human N-RAS mutant melanoma, and suggests that the increased melanomagenecity of N-RasQ61R over N-RasG12D is due to heightened abundance of the active, GTP-bound form rather than differences in the engagement of downstream effector pathways.
