Apoptosis of human melanoma cells induced by inhibition of B-RAFV600E involves preferential splicing of bimS.
Apoptosis of human melanoma cells induced by inhibition of B-RAFV600E involves preferential splicing of bimS.
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通过抑制B-RAFV600E诱导的人类黑色素瘤细胞的凋亡涉及BIMS的优先剪接。
DOI：
10.1038/cddis.2010.48
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发表时间：
2010-09-02
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
已知Bim通过抑制RAF/MEK/ERK途径在杀死黑素瘤细胞中是关键的。然而，最有效的骨化诱导亚型的Bim，BimS的潜在作用，仍然在很大程度上未得到重视。在这里，我们表明，抑制突变B-RAFV 600 E触发优先剪接产生BimS，这是特别重要的诱导B-RAFV 600 E黑色素瘤细胞凋亡。尽管特异性B-RAFV 600 E抑制剂PLX 4720在B-RAFV 600 E黑素瘤细胞中在蛋白质和mRNA水平上上调Bim、BimEL、BimL和BimS的所有三种主要同种型，但BimS mRNA与BimEL和BimL mRNA的比率的增加表明其有利于BimS剪接。一致地，在野生型B-RAF黑素瘤细胞和黑素细胞中B-RAFV 600 E的强制表达抑制BimS表达。剪接因子SRp 55似乎是BimS剪接增加所必需的，因为SRp 55被上调，并且小干扰RNA对其的抑制阻断了PLX 4720诱导的BimS诱导和细胞凋亡。PLX 4720诱导的SRp 55介导的BimS剪接增加也反映在新鲜分离的B-RAFV 600 E黑素瘤细胞中。这些结果确定了PLX 4720诱导细胞凋亡的关键机制，并且对于使黑素瘤细胞对B-RAFV 600 E抑制剂敏感具有指导意义。
Bim is known to be critical in killing of melanoma cells by inhibition of the RAF/MEK/ERK pathway. However, the potential role of the most potent apoptosis-inducing isoform of Bim, BimS, remains largely unappreciated. Here, we show that inhibition of the mutant B-RAFV600E triggers preferential splicing to produce BimS, which is particularly important in induction of apoptosis in B-RAFV600E melanoma cells. Although the specific B-RAFV600E inhibitor PLX4720 upregulates all three major isoforms of Bim, BimEL, BimL, and BimS, at the protein and mRNA levels in B-RAFV600E melanoma cells, the increase in the ratios of BimS mRNA to BimEL and BimL mRNA indicates that it favours BimS splicing. Consistently, enforced expression of B-RAFV600E in wild-type B-RAF melanoma cells and melanocytes inhibits BimS expression. The splicing factor SRp55 appears necessary for the increase in BimS splicing, as SRp55 is upregulated, and its inhibition by small interfering RNA blocks induction of BimS and apoptosis induced by PLX4720. The PLX4720-induced, SRp55-mediated increase in BimS splicing is also mirrored in freshly isolated B-RAFV600E melanoma cells. These results identify a key mechanism for induction of apoptosis by PLX4720, and are instructive for sensitizing melanoma cells to B-RAFV600E inhibitors.
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影响因子：
4.3
作者：
Cartlidge, Robert A.;Thomas, G. R.;McMahon, Martin
通讯作者：
McMahon, Martin
影响因子：
37.3
作者：
Liu H;Jiang CC;Lavis CJ;Croft A;Dong L;Tseng HY;Yang F;Tay KH;Hersey P;Zhang XD
通讯作者：
Zhang XD
影响因子：
64.8
作者：
Matter, N;Herrlich, P;König, H
通讯作者：
König, H
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：
11.5
作者：
Panka, DJ;Atkins, MB;Mier, JW
通讯作者：
Mier, JW