Regulation of cell morphology and adhesion by the tuberous sclerosis complex (TSC1/2) gene products in human kidney epithelial cells through increased E-cadherin/beta-catenin activity.
We investigated the effects of overexpression of the tuberous sclerosis-1 and -2 (TSC1/2) gene products (hamartin and tuberin, respectively) in the human kidney epithelial cell line 293 with an inducible expression system. As we had observed previously in fibroblasts, 293 cells overexpressing hamartin and/or tuberin grew more slowly in vitro. However, here we also observed that the 293 overexpressing cells underwent a dramatic morphological change in which groups of cells formed compact clusters. The overexpressing cells also displayed decreased dissociation and increased reaggregation in vitro. These changes were found to be associated with an increased level of E-cadherin, which is known to regulate cell-cell interactions in epithelial cells, and of its binding partner beta-catenin. Consistent with the role of E-cadherin in these effects, we found that the observed changes in 293 cell morphology, dissociation, and adhesion were calcium-dependent, and were reproduced by overexpression of E-cadherin. In contrast, overexpression of TSC1 in rat embryo fibroblasts, which lack E-cadherin, failed to elicit the same changes as in 293 cells. We conclude that the hamartin/tuberin complex exerted a direct effect on the morphology and adhesive properties of 293 cells through regulation of the level and/or activity of cellular E-cadherin/beta-catenin.
Li
Shaowei
S
Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Braverman
Richard
R
Li
Hongzhen
H
Vass
William C
WC
Lowy
Douglas R
DR
DeClue
Jeffrey E
JE
D000818:Animals; D015820:Cadherins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D002999:Clone Cells; D003598:Cytoskeletal Proteins / Q000187:drug effects / Q000378:metabolism*; D004441:Ecdysterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D051176:beta Catenin
C495270:CTNNB1 protein, human; D015820:Cadherins; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D011506:Proteins; D012097:Repressor Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D015534:Trans-Activators; C000624652:Tsc1 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; C055348:muristerone A; D004441:Ecdysterone; D002118:Calcium