CRTC1/MAML2 gain-of-function interactions with MYC create a gene signature predictive of cancers with CREB-MYC involvement
CRTC1/MAML2 gain-of-function interactions with MYC create a gene signature predictive of cancers with CREB-MYC involvement
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DOI：
10.1073/pnas.1319176111
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发表时间：
2014-08-12
影响因子：
11.1
通讯作者：
Conkright, Michael D.
中科院分区：
文献类型：
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作者：
Amelio, Antonio L.;Fallahi, Mohammad;Conkright, Michael D.
由染色体易位产生的嵌合癌蛋白是与肿瘤发生相关的最常见的基因突变之一。恶性粘液表皮样唾液腺肿瘤，以及越来越多的实体上皮来源的肿瘤，可以从复发性T（11，19）（第二十一题; p13.1）易位，产生一种不寻常的嵌合cAMP反应元件结合蛋白（CREB）调节的转录共激活因子1（CRTC 1）/主谋样2（MAML 2）（C1/M2）癌蛋白，CRTC 1和NOTCH/RBPJ共活化剂MAML 2。因此，C1/M2癌蛋白诱导CREB和NOTCH靶基因的异常表达。令人惊讶的是，在这里，我们报告了C1/M2癌蛋白的功能获得性活性，该活性指导其与髓细胞瘤病癌基因（MYC）蛋白的相互作用以及MYC转录靶点的激活，包括参与细胞生长和代谢、存活和肿瘤发生的靶点。这些结果在携带t（11，19）（q21; p13.1）易位并表达C1/M2癌蛋白的人粘液表皮样肿瘤细胞中得到验证。值得注意的是，C1/M2-MYC相互作用是C1/M2驱动的细胞转化所必需的，并且C1/M2转录特征预测了具有MYC和CREB联合参与的其他人类恶性肿瘤。这些发现表明，这种功能获得性特性也可能在人类癌症中发现的其他癌蛋白融合体中表现出来，并且靶向C1/M2-MYC界面的药物代表了在携带t（11，19）易位的肿瘤中开发有效和安全的抗癌疗法的有吸引力的策略。
Chimeric oncoproteins created by chromosomal translocations are among the most common genetic mutations associated with tumorigenesis. Malignant mucoepidermoid salivary gland tumors, as well as a growing number of solid epithelial-derived tumors, can arise from a recurrent t(11, 19)(q21;p13.1) translocation that generates an unusual chimeric cAMP response element binding protein (CREB)-regulated transcriptional coactivator 1 (CRTC1)/mastermind-like 2 (MAML2) (C1/M2) oncoprotein comprised of two transcriptional coactivators, the CRTC1 and the NOTCH/RBPJ coactivator MAML2. Accordingly, the C1/M2 oncoprotein induces aberrant expression of CREB and NOTCH target genes. Surprisingly, here we report a gain-of-function activity of the C1/M2 oncoprotein that directs its interactions with myelocytomatosis oncogene (MYC) proteins and the activation of MYC transcription targets, including those involved in cell growth and metabolism, survival, and tumorigenesis. These results were validated in human mucoepidermoid tumor cells that harbor the t (11, 19)(q21; p13.1) translocation and express the C1/M2 oncoprotein. Notably, the C1/M2-MYC interaction is necessary for C1/M2-driven cell transformation, and the C1/M2 transcriptional signature predicts other human malignancies having combined involvement of MYC and CREB. These findings suggest that such gain-of-function properties may also be manifest in other oncoprotein fusions found in human cancer and that agents targeting the C1/M2-MYC interface represent an attractive strategy for the development of effective and safe anticancer therapeutics in tumors harboring the t (11, 19) translocation.