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Distinct promoters mediate constitutive and inducible Bcl-XL expression in malignant lymphocytes

Oncogene volume 26, pages 1910–1919 (2007)Cite this article

Abstract

Bcl-XL is a Bcl-2-related survival protein that is essential for normal development. Bcl-XL expression is rapidly induced by a wide range of survival signals and many cancer cells constitutively express high levels. The Bcl-X gene has a complex organization with multiple promoters giving rise to RNAs with alternate 5′ non-coding exons. Here we have investigated the mechanisms that control basal and induced expression of Bcl-XL in B-lymphoma cells. Antisense experiments demonstrated that Bcl-XL was essential for survival of Akata6 B-lymphoma cells. The levels of RNAs containing the IB Bcl-X non-coding exon, derived from the distal 1B promoter, correlated with basal expression of Bcl-XL in primary malignant B cells and this promoter was highly active in B-cell lines. The activity of this promoter was largely dependent on a single Ets binding site and Ets family proteins were bound at this promoter in intact cells. CD40 ligand (CD40L)-induced cell survival was associated with increased Bcl-XL expression and accumulation of exon IA-containing RNAs, derived from the proximal 1A promoter. Nuclear factor-kappaB (NF-κB) inhibition prevented induction of Bcl-XL protein and exon IA-containing RNAs by CD40L. Therefore, the distal Bcl-X 1B promoter plays a critical role in driving constitutive expression-mediated via Ets family proteins in malignant B cells, whereas NF-κB plays a central role in the induction of Bcl-XL in response to CD40 signalling via the proximal 1A promoter.

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Acknowledgements

We thank Paul Townsend for his helpful comments. We thank Professor Paul Farrell for the kind gift of Akata6 cells and Immunex Corp., USA for the kind gift of CD40L. This work was supported by the Leukaemia Research Fund and Cancer Research UK.

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Authors and Affiliations

  1. Cancer Sciences Division, Cancer Research UK Clinical Centre, Cancer Research UK Clinical Centre, University of Southampton School of Medicine, Southampton General Hospital, Southampton, UK

    F Habens, A S Lapham, C L Dallman, B M Pickering, J Michels, P W M Johnson & G Packham

  2. Antisense Drug Discovery, ISIS Pharmaceuticals, Carlsbad, CA, USA

    E G Marcusson

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  1. F Habens
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  2. A S Lapham
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Correspondence to G Packham.

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Habens, F., Lapham, A., Dallman, C. et al. Distinct promoters mediate constitutive and inducible Bcl-XL expression in malignant lymphocytes. Oncogene 26, 1910–1919 (2007). https://doi.org/10.1038/sj.onc.1209979

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