title: ITF-2, a downstream target of the Wnt/TCF pathway, is activated in human cancers with beta-catenin defects and promotes neoplastic transformation.
abstract: In many cancers, inactivation of the adenomatous polyposis coli (APC) or Axin tumor suppressor proteins or activating mutations in beta-catenin lead to elevated beta-catenin levels, enhanced binding of beta-catenin to T cell factor (TCF) proteins, and increased expression of TCF-regulated genes. We found that the gene for the basic helix-loop-helix transcription factor ITF-2 (immunoglobulin transcription factor-2) was activated in rat E1A-immortalized RK3E cells following neoplastic transformation by beta-catenin or ligand-induced activation of a beta-catenin-estrogen receptor fusion protein. Human cancers with beta-catenin regulatory defects had elevated ITF-2 expression, and ITF-2 was repressed by restoring wild-type APC function or inhibiting TCF activity. Of note, ITF-2 promoted neoplastic transformation of RK3E cells. We propose that ITF-2 is a TCF-regulated gene, which functions in concert with other TCF target genes to promote growth and/or survival of cancer cells with defects in beta-catenin regulation.
authors.affiliation: Department of Internal Medicine, Division of Medical Genetics and the Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Frank T
authors.initials: FT
authors.lastname: Kolligs
authors.forename: Marvin T
authors.initials: MT
authors.lastname: Nieman
authors.forename: Ira
authors.initials: I
authors.lastname: Winer
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
authors.forename: David
authors.initials: D
authors.lastname: Van Mater
authors.forename: Ying
authors.initials: Y
authors.lastname: Feng
authors.forename: Ian M
authors.initials: IM
authors.lastname: Smith
authors.forename: Rong
authors.initials: R
authors.lastname: Wu
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhai
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Cho
authors.forename: Eric R
authors.initials: ER
authors.lastname: Fearon
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000378:metabolism*; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C491192:Tcf4 protein, rat; C553059:Tcf7l2 protein, rat; D015534:Trans-Activators; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin