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.
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.
Nijman
Sebastian M B
SMB
Division of Molecular Carcinogenesis and Centre for Biomedical Genetics, The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands.
Hijmans
E Marielle
EM
Division of Molecular Carcinogenesis and Centre for Biomedical Genetics, The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands.
Messaoudi
Selma El
SE
Institut de Genetique Moleculaire, Unité Mixte de Recherche 5535/IFR24 CNRS, 1919 Route de Mende 34293, Montpellier Cedex 5, France.
van Dongen
Miranda M W
MMW
Division of Molecular Carcinogenesis and Centre for Biomedical Genetics, The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands.
Sardet
Claude
C
Institut de Genetique Moleculaire, Unité Mixte de Recherche 5535/IFR24 CNRS, 1919 Route de Mende 34293, Montpellier Cedex 5, France.
Bernards
René
R
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.
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
D019927:Cyclin E; D018076:DNA, Complementary; D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta