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

Distinct promoters mediate constitutive and inducible Bcl-X-L expression in malignant lymphocytes
Distinct promoters mediate constitutive and inducible Bcl-X-L expression in malignant lymphocytes
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.
transcription factor, b cell, bcl-x-l, gene-expression, lymphoma, expression, hematopoietic malignancies, cd40, single, binding, nf-kappa-b, gene, family proteins, cell-death, time, induced apoptosis, cancer-cells, ets, development, cell, phosphatidylinositol 3-kinase, survival, rel, protein, mechanism, promoter, cancer, b-cells, families, transcription, epstein-barr-virus, poor-prognosis, cells, induction
0950-9232
1910-1919
Habens, F.
3e4cce4b-4521-4702-9582-f817d25aad37
Lapham, A.S.
124d8916-3c26-4d36-9678-e340016312bd
Dallman, C.L.
ef0f1787-ca9a-498e-a430-5ba3a97e2d6d
Pickering, B.M.
33fb6c48-ca72-4e0f-9a54-9cab462c1c16
Michels, J.
01124646-b096-4cec-86c9-2cbddaad8e74
Marcusson, E.G.
909d2eeb-bd17-41a8-a9de-9b0656ddef20
Johnson, P.W.M.
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Packham, G.
fdabe56f-2c58-469c-aadf-38878f233394
Habens, F.
3e4cce4b-4521-4702-9582-f817d25aad37
Lapham, A.S.
124d8916-3c26-4d36-9678-e340016312bd
Dallman, C.L.
ef0f1787-ca9a-498e-a430-5ba3a97e2d6d
Pickering, B.M.
33fb6c48-ca72-4e0f-9a54-9cab462c1c16
Michels, J.
01124646-b096-4cec-86c9-2cbddaad8e74
Marcusson, E.G.
909d2eeb-bd17-41a8-a9de-9b0656ddef20
Johnson, P.W.M.
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Packham, G.
fdabe56f-2c58-469c-aadf-38878f233394

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).

Record type: Article

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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More information

Published date: 2007
Keywords: transcription factor, b cell, bcl-x-l, gene-expression, lymphoma, expression, hematopoietic malignancies, cd40, single, binding, nf-kappa-b, gene, family proteins, cell-death, time, induced apoptosis, cancer-cells, ets, development, cell, phosphatidylinositol 3-kinase, survival, rel, protein, mechanism, promoter, cancer, b-cells, families, transcription, epstein-barr-virus, poor-prognosis, cells, induction

Identifiers

Local EPrints ID: 62762
URI: http://eprints.soton.ac.uk/id/eprint/62762
ISSN: 0950-9232
PURE UUID: 3e127e62-bf2a-468c-adae-23e04dad5f04
ORCID for P.W.M. Johnson: ORCID iD orcid.org/0000-0003-2306-4974
ORCID for G. Packham: ORCID iD orcid.org/0000-0002-9232-5691

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Date deposited: 09 Sep 2008
Last modified: 16 Mar 2024 03:14

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Contributors

Author: F. Habens
Author: A.S. Lapham
Author: C.L. Dallman
Author: B.M. Pickering
Author: J. Michels
Author: E.G. Marcusson
Author: P.W.M. Johnson ORCID iD
Author: G. Packham ORCID iD

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