The Msi Family of RNA-Binding Proteins Function Redundantly as Intestinal Oncoproteins.
The Msi Family of RNA-Binding Proteins Function Redundantly as Intestinal Oncoproteins.
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DOI：
10.1016/j.celrep.2015.11.022
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发表时间：
2015-12-22
期刊：
影响因子：
8.8
通讯作者：
Lengner CJ
中科院分区：
文献类型：
--
作者：
Li N;Yousefi M;Nakauka-Ddamba A;Li F;Vandivier L;Parada K;Woo DH;Wang S;Naqvi AS;Rao S;Tobias J;Cedeno RJ;Minuesa G;Y K;Barlowe TS;Valvezan A;Shankar S;Deering RP;Klein PS;Jensen ST;Kharas MG;Gregory BD;Yu Z;Lengner CJ
RNA结合蛋白Msi家族的成员最近在一系列恶性肿瘤中作为有效的癌蛋白出现。MSI 2在疾病维持所需的造血系统癌症中高度表达。与造血系统相反，结肠直肠癌可以表达Msi家族成员MSI 1和MSI 2。在这里，我们表明，在肠上皮，Msi 1和Msi 2具有类似的致癌作用。此外，Msi 1/2诱导的基因表达程序的比较和Msi 1/2-RNA结合靶点的全转录组分析揭示了显著的功能重叠，包括PDK-Akt-mTORC 1轴的诱导。最后，我们证明了MSI家族成员功能的同时丧失足以消除人结直肠癌细胞的生长，并且Msi基因缺失抑制了几种小鼠肠癌模型中的肿瘤发生。我们的研究结果表明，MSI 1和MSI 2作为功能冗余的癌蛋白所需的个体发生的肠癌。
Members of Msi family of RNA binding proteins have recently emerged as potent oncoproteins in a range of malignancies. MSI2 is highly expressed in hematopoietic cancers where it is required for disease maintenance. In contrast to the hematopoietic system, colorectal cancers can express both Msi family members, MSI1 and MSI2. Here we demonstrate that in the intestinal epithelium, Msi1 and Msi2 have analogous oncogenic effects. Further, comparison of Msi1/2-induced gene expression programs and transcriptome-wide analyses of Msi1/2-RNA binding targets reveal significant functional overlap, including induction of the PDK-Akt-mTORC1 axis. Ultimately, we demonstrate that concomitant loss of function of both MSI family members is sufficient to abrogate the growth of human colorectal cancer cells, and Msi gene deletion inhibits tumorigenesis in several mouse models of intestinal cancer. Our findings demonstrate that MSI1 and MSI2 act as functionally redundant oncoproteins required for the ontogeny of intestinal cancers.