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Human Molecular Genetics, 2003, Vol. 12, No. 14 1661-1669
DOI: 10.1093/hmg/ddg178
© 2003 Oxford University Press

Upregulation of the transcription factor TFEB in t(6;11)(p21;q13)-positive renal cell carcinomas due to promoter substitution

Roland P. Kuiper1,*, Marga Schepens1, José Thijssen1, Martien van Asseldonk1, Eva van den Berg2, Julia Bridge3, Ed Schuuring4, Eric F.P.M. Schoenmakers1 and Ad Geurts van Kessel1

1Department of Human Genetics, University Medical Center Nijmegen, PO Box 9101, 6500 HB, Nijmegen, The Netherlands, 2Department of Medical Genetics, University of Groningen, Antonius Deusinglaan 4, 9713 AW Groningen, The Netherlands, 3Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NB 68198, USA and 4Department of Pathology, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands

Received March 4, 2003; Revised April 29, 2003; Accepted May 9, 2003

The MITF/TFE subfamily of basic helix–loop–helix leucine-zipper (bHLH-LZ) transcription factors consists of four closely related members, TFE3, TFEB, TFEC and MITF, which can form both homo- and heterodimers. Previously, we demonstrated that in t(X;1)(p11;q21)-positive renal cell carcinomas (RCCs), the TFE3 gene on the X chromosome is disrupted and fused to the PRCC gene on chromosome 1. Here we show that in t(6;11)(p21;q13)-positive RCCs the TFEB gene on chromosome 6 is fused to the Alpha gene on chromosome 11. The AlphaTFEB fusion gene appears to contain all coding exons of the TFEB gene linked to 5' upstream regulatory sequences of the Alpha gene. Quantitative PCR analysis revealed that AlphaTFEB mRNA levels are up to 60-fold upregulated in primary tumor cells as compared with wild-type TFEB mRNA levels in normal kidney samples, resulting in a dramatic upregulation of TFEB protein levels. Additional transfection studies revealed that the TFEB protein encoded by the AlphaTFEB fusion gene is efficiently targeted to the nucleus. Based on these results we conclude that the RCC-associated t(6;11)(p21;q13) translocation leads to a dramatic transcriptional and translational upregulation of TFEB due to promoter substitution, thereby severely unbalancing the nuclear ratios of the MITF/TFE subfamily members. We speculate that this imbalance may lead to changes in the expression of downstream target genes, ultimately resulting in the development of RCC. Moreover, since this is the second MITF/TFE transcription factor that is involved in RCC development, our findings point towards a concept in which this bHLH-LZ subfamily may play a critical role in the regulation of (aberrant) renal cellular growth.

* To whom correspondence should be addressed. Tel: +31 243614017; Fax: +31 243540488; Email: r.kuiper{at}antrg.umcn.nl


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