Suppression of protein kinase C and the stimulation of glucocorticoid receptor synthesis by dexamethasone in human fibroblasts derived from tumor tissue.
Exposure of fibroblasts derived from keloid tissues, desmoid and dermal tissue from individuals with Gardner's syndrome (GS) to dexamethasone resulted in the suppression of protein kinase C (PKC) activity and [3H]thymidine incorporation into DNA, and a 20-fold induction of glutamine synthetase activity. Treatment of GS and keloid fibroblasts with 0.1 microM dexamethasone for 36 h increased glucocorticoid receptor (GR) synthesis, as determined by [35S]methionine labeling and immunoprecipitation with a monoclonal antibody to the human GR. The suppression of PKC activity by dexamethasone was shown to result from a loss of protein mass as determined by immunoblotting using an antibody to PKC type III. In contrast to these results, exposure of fibroblasts isolated from normal tissues to dexamethasone did not result in the suppression PKC and [3H]thymidine incorporation, there was only a sixfold induction of glutamine synthetase, and a decrease of GR synthesis. As no primary receptor binding defect could be detected, the altered response of tumor cells to steroid-occupied receptor indicates a partial post-receptor binding defect in GS and keloid cells.
Gadson
P
P
Department of Anatomy, Medical College of Georgia School of Medicine, Augusta 30912-2000.
McCoy
J
J
Wikström
A C
AC
Gustafsson
J A
JA
D000621:Aminoisobutyric Acids / Q000378:metabolism; D001692:Biological Transport; D004247:DNA / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology*; D015536:Down-Regulation; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D006801:Humans; D011493:Protein Kinase C / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013941:Thymine / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000621:Aminoisobutyric Acids; D011965:Receptors, Glucocorticoid; C017911:2-(methylamino)isobutyric acid; D003907:Dexamethasone; D004247:DNA; D011493:Protein Kinase C; D005974:Glutamate-Ammonia Ligase; D013755:Tetradecanoylphorbol Acetate; D013941:Thymine