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  • Original Paper
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The v-ErbA oncoprotein quenches the activity of an erythroid-specific enhancer

Oncogene volume 20, pages 775–787 (2001)Cite this article

Abstract

v-ErbA is a mutated variant of thyroid hormone receptor (TRα/NR1A1) borne by the Avian Erythroblastosis virus causing erythroleukemia. TRα is known to activate transcription of specific genes in the presence of its cognate ligand, T3 hormone, while in its absence it represses it. v-ErbA is unable to bind ligand, and hence is thought to contribute to leukemogenesis by actively repressing erythroid-specific genes such as the carbonic anhydrase II gene (CA II). In the prevailing model, v-ErbA occludes liganded TR from binding to its cognate elements and constitutively interacts with the corepressors NCoR/SMRT. We previously identified a v-ErbA responsive element (VRE) within a DNase I hypersensitive region (HS2) located in the second intron of the CA II gene. We now show that HS2 fulfils all the requirements for a genuine enhancer that functions independent of its orientation and position with a profound erythroid-specific activity in normal erythroid progenitors (T2ECs) and in leukemic erythroid cell lines. We find that the HS2 enhancer activity is governed by two adjacent GATA-factor binding sites. v-ErbA as well as unliganded TR prevent HS2 activity by nullifying the positive function of factors bound to GATA-sites. However, v-ErbA, in contrast to TR, does not convey active repression to silence the transcriptional activity intrinsic to a heterologous tk promoter. We propose that depending on the sequence and context of the binding site, v-ErbA contributes to leukomogenesis by occluding liganded TR as well as unliganded TR thereby preventing activation or repression, respectively.

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Acknowledgements

We thank Joan Betz and members of the Stunnenberg lab for continued discussions and critical reading of the manuscript, and thank Stefan van den Akker for assistance. We also thank Aria Baniahmad for kindly providing us with L cells and the F2-tk construct, Sjaak Philipsen for MEL cells and Carl Figdor for K562 cells.

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Author notes

  1. Paolo Ciana

    Present address: Institute of Pharmacological Sciences, University of Milan, Via Balzaretti 9, Milan, 20133, Italy

Authors and Affiliations

  1. Department of Molecular Biology, NCMLS University of Nijmegen, Geert Groote plein 26 PO Box 9101, Nijmegen, 6500 HB, The Netherlands

    Georgia G Braliou, Paolo Ciana, Willem Klaassen & Hendrik G Stunnenberg

  2. Centre de génétique moléculaire et cellulaire, UMR CNRS 5534, Université Claude Bernard Lyon I, Bat 741, 43, boulevard du 11 Novembre 1918, Villeurbanne, Cedex, 69622, France

    Olivier Gandrillon

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  1. Georgia G Braliou
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Braliou, G., Ciana, P., Klaassen, W. et al. The v-ErbA oncoprotein quenches the activity of an erythroid-specific enhancer. Oncogene 20, 775–787 (2001). https://doi.org/10.1038/sj.onc.1204159

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