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

Roland P. Kuiper, Marga Schepens, José Thijssen, Martien van Asseldonk, Eva van den Berg, Julia Bridge, Ed Schuuring, Eric F P M Shoenmakers, Ad Geurts van Kessel

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1661-1669
Number of pages9
JournalHuman Molecular Genetics
Volume12
Issue number14
DOIs
StatePublished - Jul 15 2003

Fingerprint

Renal Cell Carcinoma
Transcription Factors
Up-Regulation
Polytetrafluoroethylene
Genes
Gene Fusion
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Microphthalmia-Associated Transcription Factor
Kidney
Leucine Zippers
X-Linked Genes
Messenger RNA
Chromosomes, Human, Pair 11
Chromosomes, Human, Pair 6
Chromosomes, Human, Pair 1
Transfection
Exons
Proteins
Polymerase Chain Reaction
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Kuiper, R. P., Schepens, M., Thijssen, J., van Asseldonk, M., van den Berg, E., Bridge, J., ... van Kessel, A. G. (2003). Upregulation of the transcription factor TFEB in t(6;11)(p21;q13)-positive renal cell carcinomas due to promoter substitution. Human Molecular Genetics, 12(14), 1661-1669. https://doi.org/10.1093/hmg/ddg178

Upregulation of the transcription factor TFEB in t(6;11)(p21;q13)-positive renal cell carcinomas due to promoter substitution. / Kuiper, Roland P.; Schepens, Marga; Thijssen, José; van Asseldonk, Martien; van den Berg, Eva; Bridge, Julia; Schuuring, Ed; Shoenmakers, Eric F P M; van Kessel, Ad Geurts.

In: Human Molecular Genetics, Vol. 12, No. 14, 15.07.2003, p. 1661-1669.

Research output: Contribution to journalArticle

Kuiper, RP, Schepens, M, Thijssen, J, van Asseldonk, M, van den Berg, E, Bridge, J, Schuuring, E, Shoenmakers, EFPM & van Kessel, AG 2003, 'Upregulation of the transcription factor TFEB in t(6;11)(p21;q13)-positive renal cell carcinomas due to promoter substitution', Human Molecular Genetics, vol. 12, no. 14, pp. 1661-1669. https://doi.org/10.1093/hmg/ddg178
Kuiper, Roland P. ; Schepens, Marga ; Thijssen, José ; van Asseldonk, Martien ; van den Berg, Eva ; Bridge, Julia ; Schuuring, Ed ; Shoenmakers, Eric F P M ; van Kessel, Ad Geurts. / Upregulation of the transcription factor TFEB in t(6;11)(p21;q13)-positive renal cell carcinomas due to promoter substitution. In: Human Molecular Genetics. 2003 ; Vol. 12, No. 14. pp. 1661-1669.
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AU - van den Berg, Eva

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AU - Schuuring, Ed

AU - Shoenmakers, Eric F P M

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