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An Essential Role of Alternative Splicing of c-myc Suppressor FUSE-Binding Protein–Interacting Repressor in Carcinogenesis

Departments of ¹ Frontier Surgery, ² Molecular Diagnosis, and ³ Molecular Pathology, Graduate School of Medicine, Chiba University, Inohana, Chiba, Japan and ⁴ Laboratory of Pathology, Division of Clinical Sciences, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Takeshi Tomonaga, Department of Molecular Diagnosis (F8), Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan 260-8670. Phone: 81-43-226-2167; Fax: 11-81-43-226-2169; E-mail: tomonaga{at}faculty.chiba-u.jp.

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. (Cancer Res 2006; 66(3): 1409-17)

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