An essential role of alternative splicing of c-myc suppressor FUSE-binding protein-interacting repressor in carcinogenesis
An essential role of alternative splicing of c-myc suppressor FUSE-binding protein-interacting repressor in carcinogenesis
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DOI：
10.1158/0008-5472.can-04-4459
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发表时间：
2006-02-01
期刊：
影响因子：
11.2
通讯作者：
Ochiai, T
中科院分区：
文献类型：
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作者：
Matsushita, K;Tomonaga, T;Ochiai, T
在广泛的人类癌症中检测到c-myc的表达升高，表明该癌基因在肿瘤发展中起关键作用。最近，FUSE结合蛋白相互作用阻遏物（FIR）和TFIIH/p89/XPB解旋酶之间的相互作用被发现抑制c-myc转录，并可能是重要的抑制肿瘤的形成。在这项研究中，我们发现，FIR的强制表达诱导细胞凋亡。删除FIR的NH 2-末端抑制结构域拯救细胞免于凋亡，c-Myc与FIR的共表达也是如此;因此，Myc的抑制介导FIR驱动的凋亡。令人惊讶的是，FIR的剪接变异体不能抑制c-myc或驱动细胞凋亡，经常发现在人类原发性结直肠癌，而不是在邻近的正常组织。在HeLa细胞或结肠癌细胞系SW 480中，这种剪接变体与阻遏物感受态FIR的共表达不仅废除了c-Myc抑制，而且抑制了细胞凋亡。这些结果强烈表明，这种剪接变体的表达通过使FIR抑制失效并维持高水平的c-Myc和对抗结直肠癌中的细胞凋亡来促进肿瘤发展。
Elevated expression of c-myc has been detected in a broad range of human cancers, indicating a key role for this oncogene in tumor development. Recently, an interaction between FUSE-binding protein-interacting repressor (FIR) and TFIIH/p89/XPB helicase was found to repress c-myc transcription and might be important for suppressing tumor formation. In this study, we showed that enforced expression of FIR induced apoptosis. Deletion of the NH2-terminal repression domain of FIR rescued the cells from apoptosis as did coexpression of c-Myc with FIR; thus, repression of Myc mediates FIR-driven apoptosis. Surprisingly, a splicing variant of FIR unable to repress c-myc or to drive apoptosis was frequently discovered in human primary colorectal cancers but not in the adjacent normal tissues. Coexpression of this splicing variant with repressor-competent FIR, either in HeLa cells or in the colon cancer cell line SW480, not only abrogated c-Myc suppression but also inhibited apoptosis. These results strongly suggest the expression of this splicing variant promotes tumor development by disabling FIR repression and sustaining high levels of c-Myc and opposing apoptosis in colorectal cancer.