Expression of alpha-catenin in alpha-catenin-deficient cells increases resistance to sphingosine-induced apoptosis.
Alpha-catenin, an intracellular protein, associates with the COOH-terminal region of cadherin cell adhesion molecules through interactions with either beta-catenin or gamma-catenin (plakoglobin). The full activity of cadherins requires a linkage to the actin cytoskeleton mediated by catenins. We transfected alpha-catenin-deficient colon carcinoma cells with a series of alpha-catenin constructs to determine that alpha-catenin expression increases the resistance to apoptosis induced by sphingosine. Two groups of constructs, containing deletions in either the middle segment of the molecule or the COOH terminus, induced morphological changes, cell compaction, and decreases in cell death. In alpha-catenin-expressing cells, inhibition of cadherin cell adhesion by treatment with anti-E-cadherin antibodies did not decrease the cells viability. alpha-Catenin expression partially suppressed the downregulation of Bcl-xL and the activation of caspase 3. Expression of p27kip1 protein, an inhibitor of cyclin-dependent kinases, was increased by alpha-catenin expression in low density cell cultures. The increased levels of p27kip1 correlated with both increased resistance to cell death and morphological changes in transfectants containing deletion mutants. Transfection-mediated upregulation of p27kip1 decreases sphingosine-induced cell death in alpha-catenin-deficient cells. We postulate that alpha-catenin mediates transduction of signals from the cadherin-catenin complex to regulate the apoptotic cascade via p27kip1.
Matsubara
S
S
Department of Biochemistry, Faculty of Medicine, Kagoshima University, Kagoshima 890-8520, Japan. shmlmcbd@m.kufm.kagoshima-u.ac.jp
Ozawa
M
M
D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015820:Cadherins / Q000276:immunology / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002452:Cell Count; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D003110:Colonic Neoplasms; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D016296:Mutagenesis / Q000502:physiology; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D051178:alpha Catenin; D051020:bcl-X Protein
D000906:Antibodies; C494811:BCL2L1 protein, human; C495273:CTNNA1 protein, human; D015820:Cadherins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; D051178:alpha Catenin; D051020:bcl-X Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D013110:Sphingosine