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β-catenin/T-cell factor-mediated transcription is modulated by cell density in human bronchial epithelial cells

β-catenin/T-cell factor-mediated transcription is modulated by cell density in human bronchial epithelial cells
β-catenin/T-cell factor-mediated transcription is modulated by cell density in human bronchial epithelial cells
he embryonic Wnt/β-catenin (‘canonical’) pathway has been implicated in epithelial regeneration. To investigate the role of Wnt signal transduction in the airways, we characterised the expression of key pathway components in human bronchial epithelial cells (HBEC) and studied the influence of cell density on pathway activity, using sub-confluent cells in log-phase growth as a simple model of repairing epithelium. Primary HBEC and H292 bronchial epithelial cells were found to express TCF-4, TCF-3 and isoforms of LEF-1, transcription factors that are regulated by Wnt signalling. The cells also had the potential to respond to Wnt signalling through expression of several members of the Frizzled receptor family, including FZD-5 and -6. In confluent H292 cells, 20 mM lithium and 25% v/v Wnt-3a conditioned medium induced 4.5-fold (p = 0.008) and 1.4-fold (p = 0.006) increases in TOPflash activity, respectively. Under conditions of reduced cell density, TOPflash activity increased 1.8-fold (p = 0.002) in association with increased nuclear localisation of hypophosphorylated (active) β-catenin and increased cell proliferation. This up-regulation in reporter activity occurred independently of EGF receptor activation and could not be recapitulated by use of low-calcium medium to disrupt cadherin-mediated cell–cell adhesion, but was associated with changes in FZD-6 expression. We conclude that reactivation of this embryonic pathway may play an important role in bronchial epithelial regeneration, and that modulation of Fzd-6 receptors may regulate Wnt signalling at confluence. Recognising that many chronic inflammatory disorders of the airways involve epithelial damage and repair, altered Wnt signalling might contribute to disease pathogenesis or progression.
catenin, egf receptor, bronchial epithelial cells, tcf, lef-1, cell density
1357-2725
1281-1295
Steel, Mark D.
4eec21ea-3917-4ee6-9456-421475502866
Puddicombe, Sarah M.
124e2c4e-ab9a-46f3-855c-b54ed0b61cc4
Hamilton, Lynnsey M.
e013c481-745e-41fd-aa9e-ae02967fa44c
Powell, Rob M.
40855f3b-1e63-4b7a-a5d5-a23ef0cfbf03
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Holgate, Stephen T.
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Davies, Donna E.
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Collins, Jane E.
be0e66f1-3036-47fa-9d7e-914c48710ba4
Steel, Mark D.
4eec21ea-3917-4ee6-9456-421475502866
Puddicombe, Sarah M.
124e2c4e-ab9a-46f3-855c-b54ed0b61cc4
Hamilton, Lynnsey M.
e013c481-745e-41fd-aa9e-ae02967fa44c
Powell, Rob M.
40855f3b-1e63-4b7a-a5d5-a23ef0cfbf03
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Holgate, Stephen T.
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Davies, Donna E.
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Collins, Jane E.
be0e66f1-3036-47fa-9d7e-914c48710ba4

Steel, Mark D., Puddicombe, Sarah M., Hamilton, Lynnsey M., Powell, Rob M., Holloway, John W., Holgate, Stephen T., Davies, Donna E. and Collins, Jane E. (2005) β-catenin/T-cell factor-mediated transcription is modulated by cell density in human bronchial epithelial cells. International Journal of Biochemistry & Cell Biology, 37 (6), 1281-1295. (doi:10.1016/j.biocel.2004.12.010).

Record type: Article

Abstract

he embryonic Wnt/β-catenin (‘canonical’) pathway has been implicated in epithelial regeneration. To investigate the role of Wnt signal transduction in the airways, we characterised the expression of key pathway components in human bronchial epithelial cells (HBEC) and studied the influence of cell density on pathway activity, using sub-confluent cells in log-phase growth as a simple model of repairing epithelium. Primary HBEC and H292 bronchial epithelial cells were found to express TCF-4, TCF-3 and isoforms of LEF-1, transcription factors that are regulated by Wnt signalling. The cells also had the potential to respond to Wnt signalling through expression of several members of the Frizzled receptor family, including FZD-5 and -6. In confluent H292 cells, 20 mM lithium and 25% v/v Wnt-3a conditioned medium induced 4.5-fold (p = 0.008) and 1.4-fold (p = 0.006) increases in TOPflash activity, respectively. Under conditions of reduced cell density, TOPflash activity increased 1.8-fold (p = 0.002) in association with increased nuclear localisation of hypophosphorylated (active) β-catenin and increased cell proliferation. This up-regulation in reporter activity occurred independently of EGF receptor activation and could not be recapitulated by use of low-calcium medium to disrupt cadherin-mediated cell–cell adhesion, but was associated with changes in FZD-6 expression. We conclude that reactivation of this embryonic pathway may play an important role in bronchial epithelial regeneration, and that modulation of Fzd-6 receptors may regulate Wnt signalling at confluence. Recognising that many chronic inflammatory disorders of the airways involve epithelial damage and repair, altered Wnt signalling might contribute to disease pathogenesis or progression.

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More information

Published date: June 2005
Keywords: catenin, egf receptor, bronchial epithelial cells, tcf, lef-1, cell density

Identifiers

Local EPrints ID: 27438
URI: http://eprints.soton.ac.uk/id/eprint/27438
ISSN: 1357-2725
PURE UUID: 0afe527c-9590-41d9-bafd-392e97971414
ORCID for John W. Holloway: ORCID iD orcid.org/0000-0001-9998-0464
ORCID for Donna E. Davies: ORCID iD orcid.org/0000-0002-5117-2991

Catalogue record

Date deposited: 27 Apr 2006
Last modified: 16 Mar 2024 02:57

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Contributors

Author: Mark D. Steel
Author: Sarah M. Puddicombe
Author: Lynnsey M. Hamilton
Author: Rob M. Powell
Author: Donna E. Davies ORCID iD
Author: Jane E. Collins

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