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v-Jun downregulates the SPARC target gene by binding to the proximal promoter indirectly through Sp1/3

Oncogene volume 22, pages 4047–4061 (2003)Cite this article

Abstract

Transformation of chick embryo fibroblasts by the v-Jun oncoprotein correlates with a downregulation of the extracellular matrix protein SPARC and repression of the corresponding mRNA. Repression of SPARC contributes to the oncogenic process by facilitating tumor development in vivo. A proximal promoter fragment, designated −124/+16, is responsible for high constitutive activity of the SPARC gene and is the target of repression by v-Jun. In this paper, using electrophoretic mobility shift and pull-down assays in vitro, and transient transfections and chromatin immunoprecipitation assays in Sp1/3-deficient Drosophila SL2 cells and in chick embryo fibroblasts, we show that (i) Sp1 and/or Sp3 is required for constitutive activation of SPARC transcription, by binding directly to the GGA-rich −92/−57 fragment; and (ii) v-Jun does not bind −124/+16 directly, but binds to the GGA-rich fragment indirectly, most likely through a physical interaction with Sp1/3. Moreover, a transactivation-proficient v-Jun derivative, designated v-Jun/cebp/glz, which cannot bind Jun DNA motifs anymore and cannot heterodimerize, is still capable of downregulating SPARC efficiently. Taken together, these data strongly suggest that v-Jun downregulates SPARC through the formation of a DNA–Sp1/3–v-Jun, chromatin-associated complex.

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Abbreviations

CEF:

chicken embryo fibroblast

SPARC:

secreted protein, acidic, and rich in cysteine

AP1:

activating protein 1

ChIP assay:

chromatin immunoprecipitation assay

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Acknowledgements

This work was supported by grants from the Association pour la Recherche sur le Cancer (ARC; no. 9707 and no. 4398 to Marc Castellazzi), from the European Economic Community Biomedicine and Health Program (Biomed II contract no. BMH4 CT98 3505 to Marc Castellazzi and Salvatore Oliviero), from the Associazione Italiana Ricerca sul Cancro (AIRC; to Salvatore Oliviero), and from the Thomas F and Kate Miller Jeffress Foundation (to Timothy Bos). Sandrine Chamboredon was supported by fellowships from the Biomed II contract and the ARC. We thank Joel Baguet for the construction of the pBluescript II SK(+)-derived plasmid pH, Bertrand Pain for the gift of the avian cDNA library used to screen the Sp1 and Sp3 coding sequences, and Hans van Dam for the gift of the pGL2-derived tata and 1 × coll-tata plasmids.

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Authors and Affiliations

  1. Unité de Virologie Humaine, INSERM-U412, Ecole Normale Supérieure, 46 allée d'ltalie, Lyon, Cedex 07, 69364, France

    Sandrine Chamboredon, Emmanuel Vial, Julien Hurault & Marc Castellazzi

  2. Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, PO Box 1980, Norfolk, 23501, VA, USA

    Joseph Briggs & Timothy Bos

  3. Dipartimento di Biologia Molecolare, Universita degli Studi di Siena, via Fiorentina 1, Siena, 53100, Italy

    Federico Galvagni & Salvatore Oliviero

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  1. Sandrine Chamboredon
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  2. Joseph Briggs
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Correspondence to Marc Castellazzi.

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Chamboredon, S., Briggs, J., Vial, E. et al. v-Jun downregulates the SPARC target gene by binding to the proximal promoter indirectly through Sp1/3. Oncogene 22, 4047–4061 (2003). https://doi.org/10.1038/sj.onc.1206713

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