An Essential Role of Alternative Splicing of c-myc Suppressor FUSE-Binding Protein–Interacting Repressor in Carcinogenesis
2006; American Association for Cancer Research; Volume: 66; Issue: 3 Linguagem: Inglês
10.1158/0008-5472.can-04-4459
ISSN1538-7445
AutoresKazuyuki Matsushita, Takeshi Tomonaga, Hideaki Shimada, Ayumi Shioya, Morihiro Higashi, Hisahiro Matsubara, Kenichi Harigaya, Fumio Nomura, Daniel Libutti, David Levens, Takenori Ochiai,
Tópico(s)Cancer-related gene regulation
ResumoAbstract 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)
Referência(s)