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

Nijman, S. M. B.; Hijmans, E. M.; El Messaoudi, S.; van Dongen, M. M. W.; Sardet, C.; Bernards, R.

Journal of Biological Chemistry

2006-08-04 / vol 281 / pages 21582-21587


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-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.



activation; tumor-suppressor; proliferation; s-phase; transcription factor; cyclin-e; e2f; inhibition; renal-cell carcinomas; repression

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