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The Wilms' tumor gene product represses the transcription of thrombospondin 1 in response to overexpression of c-Jun

Oncogene volume 18, pages 3143–3151 (1999)Cite this article

Abstract

Thrombospondin 1 (TSP1) is known for its significant anti-angiogenic properties. In a previous study, we have shown that transient or stable overexpression of the transcription factor c-Jun, in rat fibroblasts, leads to repression of TSP1. We now demonstrate that the c-Jun-induced repression of TSP1 does not occur directly and does not require binding of c-Jun to the TSP1 promoter. Instead, repression involves a factor secreted by c-Jun-overexpressing cells. This secreted factor triggers a signal transduction pathway from the membrane to the nucleus, and these signals lead to the binding of the product of the Wilms' tumor suppressor gene, WT1, to the −210 region of the TSP1 promoter. This region binds WT1 and SP1, but not EGR1, although its sequence fits the consensus binding site for this transcription factor. WT1 overexpression in transfected cells inhibits endogenous TSP1 gene expression and TSP1 transcription in experiments using TSP1 promoter-reporter constructs. The WT1−KTS isoform is more active in repressing TSP1 transcription than WT1+KTS, while EGR1 is inactive. Enhancement of WT1 binding to DNA in response to c-Jun does not require de novo protein synthesis. The above mechanism for TSP1 repression could apply to other genes, thus coordinating their regulation in the vicinity of a c-Jun-overexpressing cell. We conclude that WT1, which was discovered as a result of its tumor suppressor properties, may also possess oncogenic characteristics in the c-Jun transformation process, and thus repress the anti-angiogenic protein, TSP1.

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Acknowledgements

We thank N Montreau for excellent technical assistance, Dr M Lacasa, Dr B Méhul, and Dr D Weil for helpful discussions and Dr A Harel-Bellan for critical review of the manuscript. We thank Dr C Jaulin for a gift of anti-SP1 antibodies, Dr MC Lang for a gift of anti-EGR1 antibodies, Dr D Haber and Dr P Charnay for WT1 and EGR1 expression vectors, Dr D Lawrence for a gift of TGFβ1 and Dr S Oliviero for a gift of FIGF/VEGF-D. This work was supported by grants from the Association pour la Recherche sur le Cancer, the Ligue Nationale Contre le Cancer and by NIH grant HL 18645 (to PB).

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  1. CNRS UPR9079, Oncogénèse, Différenciation et Transduction du Signal, 7 rue Guy Moquet, BP8, Villejuif, 94801, France

    Valérie Dejong, Armelle Degeorges, Stéphanie Filleur, Slimane Ait-Si-Ali, Amel Mettouchi, Bernard Binétruy & Florence Cabon

  2. Departments of Biochemistry and Medicine, University of Washington, Seattle, 98195, Washington, USA

    Paul Bornstein

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Dejong, V., Degeorges, A., Filleur, S. et al. The Wilms' tumor gene product represses the transcription of thrombospondin 1 in response to overexpression of c-Jun. Oncogene 18, 3143–3151 (1999). https://doi.org/10.1038/sj.onc.1202654

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