Bcl-2 expression decreases cadherin-mediated cell-cell adhesion.
Bcl-2, a member of the apoptosis-regulating family of proteins confers a survival advantage on cells by inhibiting apoptosis. Bcl-2 expression is estrogen-responsive and high in various tumors. Overexpression of Bcl-2 has been associated with the loss of contact inhibition, unregulated growth and foci formation in culture. In this study, we have examined the effects of bcl-2 overexpression and expression on cell-cell adhesion in MCF-7 and MDCK epithelial cell lines respectively. Overexpression of Bcl-2 in estrogen receptor-positive MCF-7 mammary carcinoma cells led to decreased cell surface E-cadherin and the disruption of junctional complexes concurrent with intracellular redistribution of their components. Particularly noticeable, was the partial nuclear localization of the tight junction-associated protein ZO-1 which coincided with upregulation of ErbB2. The expression of this EGF co-receptor is regulated by the ZO-1-associated transcription factor ZONAB. Growth in estrogen-depleted media led to downregulation of Bcl-2 expression and upregulation and membrane localization of all junctional proteins. Similar disruption in junctions, accompanied by decreased transepithelial resistance, was observed when Bcl-2 was expressed in MDCK cells. These results strongly suggest that Bcl-2 expression decreases the level of functional E-cadherin thereby interfering with junction formation. The inhibition of junction formation decreases cell-cell adhesion leading to the loss of contact inhibition, which, in vivo, can lead to unregulated growth and tumorigenesis.
Li
Laiji
L
Department of Cell Biology, University of Alberta, Edmonton, Alberta T6G2H7, Canada.
Backer
Jody
J
Wong
Annisa S K
AS
Schwanke
Erin L
EL
Stewart
Brian G
BG
Pasdar
Manijeh
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015820:Cadherins / Q000378:metabolism*; D051177:Catenins; D002448:Cell Adhesion / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004285:Dogs; D015536:Down-Regulation / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism* / Q000648:ultrastructure; D008565:Membrane Proteins; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin; D000095002:Delta Catenin
D015820:Cadherins; D051177:Catenins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D066246:ErbB Receptors; D004967:Estrogens; D008565:Membrane Proteins; D010750:Phosphoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D015534:Trans-Activators; D014157:Transcription Factors; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin; D000095002:Delta Catenin; C495270:CTNNB1 protein, human; C569042:TJP1 protein, human; C409302:ZONAB protein, Canis familiaris