title: Induction of a beta-catenin-LEF-1 complex by wnt-1 and transforming mutants of beta-catenin.
abstract: Signal transduction by beta-catenin involves its posttranslational stabilization and import to the nucleus where it interacts with transcription factors. Recent implications for beta-catenin signaling in cancer prompted us to examine colon cancer cell lines for the expression of LEF-1, a transcription factor that binds to beta-catenin. The analysis of several cell lines revealed the expression of LEF1 mRNA and a constitutive association of the LEF-1 protein with beta-catenin. In contrast to the colon cells, PC12 and 293 cells did not contain a beta-catenin-LEF-1 complex, even though both proteins were detected in cell lysates. In these cells, the association of endogenous LEF1 and beta-catenin was induced by stimulation with the wnt-1 proto-oncogene. The complex formed following transient stimulation with wnt-1 and also persisted in cells stably expressing wnt-1. Ectopic overexpression of beta-catenin in 293 cells also induced the assembly of the beta-catenin-LEF-1 complex and activated gene transcription from a LEF-1-dependent promotor. Expression of mutant oncogenic forms of beta-catenin identified in cancer cells resulted in higher levels of transcriptional activity. The results suggest that a cancer pathway driven by wnt-1, or mutant forms of beta-catenin, may involve the formation of a persistent transcriptionally active complex of beta-catenin and LEF1.
authors.affiliation: ONYX Pharmaceuticals, Richmond, California 94806, USA.
authors.forename: E
authors.initials: E
authors.lastname: Porfiri
authors.forename: B
authors.initials: B
authors.lastname: Rubinfeld
authors.forename: I
authors.initials: I
authors.lastname: Albert
authors.forename: K
authors.initials: K
authors.lastname: Hovanes
authors.forename: M
authors.initials: M
authors.lastname: Waterman
authors.forename: P
authors.initials: P
authors.lastname: Polakis
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D003110:Colonic Neoplasms; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D051821:Lymphoid Enhancer-Binding Factor 1; D008545:Melanoma; D051379:Mice; D009154:Mutation; D016716:PC12 Cells; D011233:Precipitin Tests; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators; D014157:Transcription Factors / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D015820:Cadherins; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C497573:LEF1 protein, human; C497574:Lef1 protein, mouse; C497575:Lef1 protein, rat; D051821:Lymphoid Enhancer-Binding Factor 1; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C495247:WNT1 protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; C495245:Wnt1 protein, rat; D029961:Zebrafish Proteins; D051176:beta Catenin