title: A functional genetic screen identifies TFE3 as a gene that confers resistance to the anti-proliferative effects of the retinoblastoma protein and transforming growth factor-beta.
abstract: The helix-loop-helix transcription factor TFE3 has been suggested to play a role in the control of cell growth by acting as a binding partner of transcriptional regulators such as E2F3, SMAD3, and LEF-1. Furthermore, translocations/TFE3 fusions have been directly implicated in tumorigenesis. Surprisingly, however, a direct functional role for TFE3 in the regulation of proliferation has not been reported. By screening retroviral cDNA expression libraries to identify cDNAs that confer resistance to a pRB-induced proliferation arrest, we have found that TFE3 overrides a growth arrest in Rat1 cells induced by pRB and its upstream regulator p16(INK4A). In addition, TFE3 expression blocks the anti-mitogenic effects of TGF-beta in rodent and human cells. We provide data supporting a role for endogenous TFE3 in the direct regulation of CYCLIN E expression in an E2F3-dependent manner. These observations establish TFE3 as a functional regulator of proliferation and offer a potential mechanism for its involvement in cancer.
authors.affiliation: Division of Molecular Carcinogenesis and Centre for Biomedical Genetics, The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands.
authors.forename: Sebastian M B
authors.initials: SMB
authors.lastname: Nijman
authors.affiliation: Division of Molecular Carcinogenesis and Centre for Biomedical Genetics, The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands.
authors.forename: E Marielle
authors.initials: EM
authors.lastname: Hijmans
authors.affiliation: Institut de Genetique Moleculaire, Unité Mixte de Recherche 5535/IFR24 CNRS, 1919 Route de Mende 34293, Montpellier Cedex 5, France.
authors.forename: Selma El
authors.initials: SE
authors.lastname: Messaoudi
authors.affiliation: Division of Molecular Carcinogenesis and Centre for Biomedical Genetics, The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands.
authors.forename: Miranda M W
authors.initials: MMW
authors.lastname: van Dongen
authors.affiliation: Institut de Genetique Moleculaire, Unité Mixte de Recherche 5535/IFR24 CNRS, 1919 Route de Mende 34293, Montpellier Cedex 5, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Sardet
authors.affiliation: Division of Molecular Carcinogenesis and Centre for Biomedical Genetics, The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands. Electronic address: r.bernards@nki.nl.
authors.forename: René
authors.initials: R
authors.lastname: Bernards
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D019927:Cyclin E / Q000235:genetics; D018076:DNA, Complementary; D050699:E2F3 Transcription Factor / Q000235:genetics / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation; D015723:Gene Library; D006801:Humans; D008907:Mink; D051381:Rats; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors* / Q000502:physiology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D019927:Cyclin E; D018076:DNA, Complementary; D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta