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

Habens, F., Lapham, A.S., Dallman, C.L., Pickering, B.M., Michels, J., Marcusson, E.G., Johnson, P.W.M. and Packham, G. (2007) Distinct promoters mediate constitutive and inducible Bcl-X-L expression in malignant lymphocytes. Oncogene, 26 (13), 1910-1919. (doi:10.1038/sj.onc.1209979).

Abstract

Bcl-X-L is a Bcl-2-related survival protein that is essential for normal development. Bcl-X-L 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-codingexons. Here we have investigated the mechanisms that control basal and induced expression of Bcl-X-L in B-lymphoma cells. Antisense experiments demonstrated that Bcl-X-L 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-X-L 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-X-L expression and accumulation of exon IA-containing RNAs, derived from the proximal 1A promoter. Nuclear factor-kappaB (NF-kappa B) inhibition prevented induction of Bcl-X-L protein and exon IA-containingRNAs 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-kappa B plays a central role in the induction of Bcl-X-L in response to CD40 signalling via the proximal 1A promoter.

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Contributors

Author: P.W.M. Johnson

Author: G. Packham

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