E-cadherin controls beta-catenin and NF-kappaB transcriptional activity in mesenchymal gene expression.
E-cadherin and its transcriptional repressor Snail1 (Snai1) are two factors that control epithelial phenotype. Expression of Snail1 promotes the conversion of epithelial cells to mesenchymal cells, and occurs concomitantly with the downregulation of E-cadherin and the upregulation of expression of mesenchymal genes such as those encoding fibronectin and LEF1. We studied the molecular mechanism controlling the expression of these genes in mesenchymal cells. Forced expression of E-cadherin strongly downregulated fibronectin and LEF1 RNA levels, indicating that E-cadherin-sensitive factors are involved in the transcription of these genes. E-cadherin overexpression decreased the transcriptional activity of the fibronectin promoter and reduced the interaction of beta-catenin and NF-kappaB with this promoter. Similar to beta-catenin, NF-kappaB was found, by co-immunoprecipitation and pull-down assays, to be associated with E-cadherin and other cell-adhesion components. Interaction of the NF-kappaB p65 subunit with E-cadherin or beta-catenin was reduced when adherens junctions were disrupted by K-ras overexpression or by E-cadherin depletion using siRNA. These conditions did not affect the association of p65 with the NF-kappaB inhibitor IkappaBalpha. The functional significance of these results was stressed by the stimulation of NF-kappaB transcriptional activity, both basal and TNF-alpha-stimulated, induced by an E-cadherin siRNA. Therefore, these results demonstrate that E-cadherin not only controls the transcriptional activity of beta-catenin but also that of NF-kappaB. They indicate too that binding of this latter factor to the adherens junctional complex prevents the transcription of mesenchymal genes.
Unitat de Biofísica-CEB, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain.
Guiomar
G
Solanas
Montserrat
M
Porta-de-la-Riva
Cristina
C
Agustí
David
D
Casagolda
Francisco
F
Sánchez-Aguilera
María Jesús
MJ
Larriba
Ferran
F
Pons
Sandra
S
Peiró
Maria
M
Escrivà
Alberto
A
Muñoz
Mireia
M
Duñach
Antonio García
AG
de Herreros
Josep
J
Baulida
D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D005353:Fibronectins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics* / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
D015820:Cadherins; D005353:Fibronectins; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D016328:NF-kappa B; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051176:beta Catenin