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-Î

• Published in: The Journal of biological chemistry 2006-08, Vol.281 (31), p.21582
• Main Authors: Sebastian M. B. Nijman, E. Marielle Hijmans, Selma El Messaoudi, Miranda M. W. van Dongen, Claude Sardet, René Bernards
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M602312200

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 ( 1 – 4 ). Furthermore, translocations/TFE3 fusions have been directly implicated in tumorigenesis ( 5 – 7 ). 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-β 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.