An essential role of alternative splicing of c-myc suppressor FUSE-binding protein-interacting repressor in carcinogenesis

Cancer Res. 2006 Feb 1;66(3):1409-17. doi: 10.1158/0008-5472.CAN-04-4459.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Apoptosis / physiology
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • DNA-Binding Proteins
  • Exons
  • Genes, myc / physiology*
  • Humans
  • Protein Isoforms
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors
  • Proto-Oncogene Proteins c-myc / biosynthesis
  • Proto-Oncogene Proteins c-myc / genetics
  • RNA Splicing Factors
  • RNA-Binding Proteins
  • Repressor Proteins
  • Up-Regulation


  • Carrier Proteins
  • DNA-Binding Proteins
  • MYC protein, human
  • Protein Isoforms
  • Proto-Oncogene Proteins c-myc
  • RNA Splicing Factors
  • RNA-Binding Proteins
  • Repressor Proteins
  • poly-U binding splicing factor 60KDa