Rottlerin induces a transformed phenotype in human keratinocytes.
PKCdelta plays a fundamental role in cell cycle control. Consistent with its proposed tumour suppressor function, ras transfection of the human keratinocyte cell line HaCaT results in a loss of PKCdelta expression mediated by TGFalpha (Exp. Cell Res., 219, 299, 1995). To get more insight into the role of PKCdelta in keratinocytes, we investigated the effects of Rottlerin, a specific inhibitor of protein kinase Cdelta, in HaCaT cells. After Rottlerin treatment, HaCaT cells lost their cobble-stone morphology and displayed a spindle-shaped, fibroblastic phenotype. Additionally, the establishment of cell-cell contacts was prevented. This was caused by an internalization of E-cadherin and beta-catenin as assessed by immunofluorescence. A similar phenotype was observed in the presence of a neutralizing anti-E-cadherin antibody. Rottlerin-treated HaCaT cells proliferated like transformed cells in a three-dimensional cell culture system. We therefore conclude that PKCdelta is involved in mediating cell-cell contacts via E-cadherin and hence regulates differentiation in HaCaT cells.
Dietrich
C
C
Institute of Toxicology, Johannes Gutenberg-University, Obere Zahlbacherstrasse 67, Mainz, 55131, Germany. cdietric@mail.uni-mainz.de
Gumpert
N
N
Heit
I
I
Borchert-Stuhlträger
M
M
Oesch
F
F
Wieser
R
R
D000098:Acetophenones / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D003260:Contact Inhibition / Q000187:drug effects / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000502:physiology; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010641:Phenotype; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000502:physiology; D051745:Protein Kinase C-delta; D015534:Trans-Activators; D051176:beta Catenin
D000098:Acetophenones; D001578:Benzopyrans; C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D015534:Trans-Activators; D051176:beta Catenin; C085746:rottlerin; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta