An essential role of alternative splicing of c-myc suppressor FUSE-binding protein-interacting repressor in carcinogenesis.
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 NH(2)-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.
Matsushita
Kazuyuki
K
Departments of Frontier Surgery, Molecular Diagnosis, and Molecular Pathology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan 160-8670.
Tomonaga
Takeshi
T
Shimada
Hideaki
H
Shioya
Ayumi
A
Higashi
Morihiro
M
Matsubara
Hisahiro
H
Harigaya
Kenichi
K
Nomura
Fumio
F
Libutti
Daniel
D
Levens
David
D
Ochiai
Takenori
T
D017398:Alternative Splicing; D017209:Apoptosis / Q000502:physiology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins; D005091:Exons; D016259:Genes, myc / Q000502:physiology*; D006801:Humans; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D015854:Up-Regulation
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C489427:MYC protein, human; D020033:Protein Isoforms; D016271:Proto-Oncogene Proteins c-myc; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C410595:poly-U binding splicing factor 60KDa