Disruption of β-catenin/CBP signaling inhibits human airway epithelial-mesenchymal transition and repair.

Moheimani, F; Roth, HM; Cross, J; Reid, AT; Shaheen, F; Warner, SM; Hirota, JA; Kicic, A; Hallstrand, TS; Kahn, M; Stick, SM; Hansbro, PM; Hackett, T-L; Knight, DA

Disruption of β-catenin/CBP signaling inhibits human airway epithelial-mesenchymal transition and repair.

Moheimani, F Roth, HM Cross, J Reid, AT Shaheen, F Warner, SM Hirota, JA Kicic, A Hallstrand, TS Kahn, M Stick, SM Hansbro, PM Hackett, T-L Knight, DA

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Publisher:: PERGAMON-ELSEVIER SCIENCE LTD
Publication Type:: Journal Article
Citation:: The international journal of biochemistry & cell biology, 2015, 68, pp. 59-69
Issue Date:: 2015-11

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Field	Value	Language
dc.contributor.author	Moheimani, F
dc.contributor.author	Roth, HM
dc.contributor.author	Cross, J
dc.contributor.author	Reid, AT
dc.contributor.author	Shaheen, F
dc.contributor.author	Warner, SM
dc.contributor.author	Hirota, JA
dc.contributor.author	Kicic, A
dc.contributor.author	Hallstrand, TS
dc.contributor.author	Kahn, M
dc.contributor.author	Stick, SM
dc.contributor.author	Hansbro, PM
dc.contributor.author	Hackett, T-L
dc.contributor.author	Knight, DA
dc.date.accessioned	2021-03-03T05:18:22Z
dc.date.available	2015-08-19
dc.date.available	2021-03-03T05:18:22Z
dc.date.issued	2015-11
dc.identifier.citation	The international journal of biochemistry & cell biology, 2015, 68, pp. 59-69
dc.identifier.issn	1357-2725
dc.identifier.issn	1878-5875
dc.identifier.uri	http://hdl.handle.net/10453/146712
dc.description.abstract	The epithelium of asthmatics is characterized by reduced expression of E-cadherin and increased expression of the basal cell markers ck-5 and p63 that is indicative of a relatively undifferentiated repairing epithelium. This phenotype correlates with increased proliferation, compromised wound healing and an enhanced capacity to undergo epithelial-mesenchymal transition (EMT). The transcription factor β-catenin plays a vital role in epithelial cell differentiation and regeneration, depending on the co-factor recruited. Transcriptional programs driven by the β-catenin/CBP axis are critical for maintaining an undifferentiated and proliferative state, whereas the β-catenin/p300 axis is associated with cell differentiation. We hypothesized that disrupting the β-catenin/CBP signaling axis would promote epithelial differentiation and inhibit EMT. We treated monolayer cultures of human airway epithelial cells with TGFβ1 in the presence or absence of the selective small molecule ICG-001 to inhibit β-catenin/CBP signaling. We used western blots to assess expression of an EMT signature, CBP, p300, β-catenin, fibronectin and ITGβ1 and scratch wound assays to assess epithelial cell migration. Snai-1 and -2 expressions were determined using q-PCR. Exposure to TGFβ1 induced EMT, characterized by reduced E-cadherin expression with increased expression of α-smooth muscle actin and EDA-fibronectin. Either co-treatment or therapeutic administration of ICG-001 completely inhibited TGFβ1-induced EMT. ICG-001 also reduced the expression of ck-5 and -19 independent of TGFβ1. Exposure to ICG-001 significantly inhibited epithelial cell proliferation and migration, coincident with a down regulation of ITGβ1 and fibronectin expression. These data support our hypothesis that modulating the β-catenin/CBP signaling axis plays a key role in epithelial plasticity and function.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	PERGAMON-ELSEVIER SCIENCE LTD
dc.relation	http://purl.org/au-research/grants/nhmrc/1064405
dc.relation.ispartof	The international journal of biochemistry & cell biology
dc.relation.isbasedon	10.1016/j.biocel.2015.08.014
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	0601 Biochemistry and Cell Biology, 1101 Medical Biochemistry and Metabolomics, 1116 Medical Physiology
dc.subject.classification	Biochemistry & Molecular Biology
dc.subject.mesh	Respiratory Mucosa
dc.subject.mesh	Epithelial Cells
dc.subject.mesh	Humans
dc.subject.mesh	Asthma
dc.subject.mesh	Pyrimidinones
dc.subject.mesh	Actins
dc.subject.mesh	Sialoglycoproteins
dc.subject.mesh	Peptide Fragments
dc.subject.mesh	Fibronectins
dc.subject.mesh	Transcription Factors
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Cell Differentiation
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	Cell Movement
dc.subject.mesh	Gene Expression Regulation
dc.subject.mesh	E1A-Associated p300 Protein
dc.subject.mesh	beta Catenin
dc.subject.mesh	Transforming Growth Factor beta1
dc.subject.mesh	Keratin-5
dc.subject.mesh	Keratin-19
dc.subject.mesh	Epithelial-Mesenchymal Transition
dc.subject.mesh	Primary Cell Culture
dc.subject.mesh	Bridged Bicyclo Compounds, Heterocyclic
dc.subject.mesh	Snail Family Transcription Factors
dc.subject.mesh	Actins
dc.subject.mesh	Asthma
dc.subject.mesh	Bridged Bicyclo Compounds, Heterocyclic
dc.subject.mesh	Cell Differentiation
dc.subject.mesh	Cell Movement
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	E1A-Associated p300 Protein
dc.subject.mesh	Epithelial Cells
dc.subject.mesh	Epithelial-Mesenchymal Transition
dc.subject.mesh	Fibronectins
dc.subject.mesh	Gene Expression Regulation
dc.subject.mesh	Humans
dc.subject.mesh	Keratin-19
dc.subject.mesh	Keratin-5
dc.subject.mesh	Peptide Fragments
dc.subject.mesh	Primary Cell Culture
dc.subject.mesh	Pyrimidinones
dc.subject.mesh	Respiratory Mucosa
dc.subject.mesh	Sialoglycoproteins
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Snail Family Transcription Factors
dc.subject.mesh	Transcription Factors
dc.subject.mesh	Transforming Growth Factor beta1
dc.subject.mesh	beta Catenin
dc.title	Disruption of β-catenin/CBP signaling inhibits human airway epithelial-mesenchymal transition and repair.
dc.type	Journal Article
utslib.citation.volume	68
utslib.location.activity	Netherlands
utslib.for	0601 Biochemistry and Cell Biology
utslib.for	1101 Medical Biochemistry and Metabolomics
utslib.for	1116 Medical Physiology
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney
utslib.copyright.status	closed_access	*
dc.date.updated	2021-03-03T05:18:18Z
pubs.publication-status	Published
pubs.volume	68

Abstract:

The epithelium of asthmatics is characterized by reduced expression of E-cadherin and increased expression of the basal cell markers ck-5 and p63 that is indicative of a relatively undifferentiated repairing epithelium. This phenotype correlates with increased proliferation, compromised wound healing and an enhanced capacity to undergo epithelial-mesenchymal transition (EMT). The transcription factor β-catenin plays a vital role in epithelial cell differentiation and regeneration, depending on the co-factor recruited. Transcriptional programs driven by the β-catenin/CBP axis are critical for maintaining an undifferentiated and proliferative state, whereas the β-catenin/p300 axis is associated with cell differentiation. We hypothesized that disrupting the β-catenin/CBP signaling axis would promote epithelial differentiation and inhibit EMT. We treated monolayer cultures of human airway epithelial cells with TGFβ1 in the presence or absence of the selective small molecule ICG-001 to inhibit β-catenin/CBP signaling. We used western blots to assess expression of an EMT signature, CBP, p300, β-catenin, fibronectin and ITGβ1 and scratch wound assays to assess epithelial cell migration. Snai-1 and -2 expressions were determined using q-PCR. Exposure to TGFβ1 induced EMT, characterized by reduced E-cadherin expression with increased expression of α-smooth muscle actin and EDA-fibronectin. Either co-treatment or therapeutic administration of ICG-001 completely inhibited TGFβ1-induced EMT. ICG-001 also reduced the expression of ck-5 and -19 independent of TGFβ1. Exposure to ICG-001 significantly inhibited epithelial cell proliferation and migration, coincident with a down regulation of ITGβ1 and fibronectin expression. These data support our hypothesis that modulating the β-catenin/CBP signaling axis plays a key role in epithelial plasticity and function.

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http://hdl.handle.net/10453/146712