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BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription

Oncogene volume 25, pages 7297–7304 (2006)Cite this article

Abstract

BCL3 is a proto-oncogene affected by chromosomal translocations in some patients with chronic lymphocytic leukemia. It is an IκB family protein that is involved in transcriptional regulation of a number of NF-κB target genes. In this study, interleukin (IL)-6-induced BCL3 expression and its effect on survival of multiple myeloma (MM) cells were examined. We demonstrate the upregulation of BCL3 by IL-6 in INA-6 and other MM cell lines. Sequence analysis of the BCL3 gene locus revealed four potential signal transducer and activator of transcription (Stat) binding sites within two conserved intronic enhancers regions: one located within enhancer HS3 and three within HS4. Chromatin immunoprecipitation experiments showed increased Stat3 binding to both enhancers upon IL-6 stimulation. Silencing Stat3 expression by small interfering RNA (siRNA) abrogated BCL3 expression by IL-6. Using reporter gene assays, we demonstrate that BCL3 transcription depends on HS4. Mutation of the Stat motifs within HS4 abolished IL-6-dependent BCL3 induction. Furthermore, BCL3 transcription was inhibited by its own gene product. This repressive feedback is mediated by NF-κB sites within the promoter and HS3. Finally, we show that overexpression of BCL3 increases apoptosis, whereas BCL3-specific siRNA does not affect the viability of INA-6 cells suggesting that BCL3 is not essential for the survival of these cells.

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Acknowledgements

We thank Claus Scheidereit for providing plasmid pCDNA-BCL3 and Stefan Rose-John for recombinant IL-6. Cell lines MM1.S and JK6-E were kindly provided by Renate Burger and Martin Gramatzki. This work was supported by the Interdisciplinary Center for Clinical Research (IZKF, project A13) at the University of Leipzig and by SFB610 (project A6) from the Deutsche Forschungsgemeinschaft.

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Authors and Affiliations

  1. Institute of Clinical Immunology and Transfusion Medicine, University of Leipzig, Leipzig, Germany

    K Brocke-Heidrich, H Cvijic, G Pfeifer, D Löffler, C Henze & F Horn

  2. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA

    B Ge & T W McKeithan

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  1. K Brocke-Heidrich
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  2. B Ge
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Correspondence to K Brocke-Heidrich.

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Brocke-Heidrich, K., Ge, B., Cvijic, H. et al. BCL3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription. Oncogene 25, 7297–7304 (2006). https://doi.org/10.1038/sj.onc.1209711

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