Blocking of tumor promoter-induced AP-1 activity inhibits induced transformation in JB6 mouse epidermal cells.
AP-1 transcriptional activity is stimulated by the transformation promoters phorbol 12-myristate 13-acetate ("12-O-tetradecanoylphorbol 13-acetate," TPA) and epidermal growth factor (EGF) in promotion-sensitive (P+) but not in promotion-resistant (P-) JB6 mouse epidermal cell lines. Although TPA stimulates expression of the jun and fos family genes, only c-jun expression shows higher elevation in P+ cells than in P- cells. The present study tests the hypothesis that induced AP-1 activity is required for tumor promoter-induced transformation in JB6 P+ cells. Both retinoic acid and the glucocorticoid fluocinolone acetonide inhibited basal and TPA-induced AP-1 activities that were tested with a stromelysin promoter-chloramphenicol acetyltransferase reporter gene in P+ cells. Since both retinoic acid and fluocinolone acetonide are active in inhibiting TPA-induced anchorage-independent transformation of P+ cells in the dose range that blocks TPA-induced AP-1 activity, their antipromoting effects may occur through inhibition of AP-1 activity. To test the hypothesis with a more specific inhibitor, stable clonal transfectants of P+ cells expressing dominant negative c-jun mutant encoding a transcriptionally inactive product were analyzed. All transfectants showed a block in TPA and EGF induction of AP-1 activity. All transfectants also showed inhibition of TPA-induced transformation, and most transfectants showed a block in EGF-induced transformation. These results indicate that AP-1 activity is required for TPA- or EGF-induced transformation. This work demonstrates that a specific block in induced AP-1 activity inhibits tumor promoter-induced transformation.
Dong
Z
Z
Biological Carcinogenesis and Development Program, PRI/DynCorp, Frederick, MD.
Birrer
M J
MJ
Watts
R G
RG
Matrisian
L M
LM
Colburn
N H
NH
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D004247:DNA / Q000235:genetics; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005446:Fluocinolone Acetonide / Q000494:pharmacology; D015870:Gene Expression; D017930:Genes, Reporter; D016762:Genes, fos / Q000187:drug effects; D016758:Genes, jun / Q000187:drug effects; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology
D016755:Proto-Oncogene Proteins c-jun; D005446:Fluocinolone Acetonide; D014212:Tretinoin; D004815:Epidermal Growth Factor; D004247:DNA; D013755:Tetradecanoylphorbol Acetate