title: c-jun and multistage carcinogenesis: association of overexpression of introduced c-jun with progression toward a neoplastic endpoint in mouse JB6 cells sensitive to tumor promoter-induced transformation.
abstract: Tumor promoters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) and epidermal growth factor (EGF) induce neoplastic transformation, elevated c-jun protein expression, and activator protein-1 (AP-1)-dependent gene expression in JB6 mouse epidermal cells sensitive to tumor promoters (clone 415a P+ cells). In contrast, JB6 cells resistant to tumor promoter-induced transformation (clone 307b P- cells) exhibit a greatly reduced TPA or EGF inducible c-jun expression and AP-1 activity. We have recently shown that induced AP-1 is necessary for tumor promoter-induced transformation of P+ cells because introduction of a dominant negative c-jun mutant into P+ cells inhibits both AP-1 dependent transactivation and the transformation response to tumor promoter. The intent of the investigation presented here was to test the hypothesis that elevation of AP-1 activity is sufficient to cause progression to the P+ phenotype in P- cells or to the transformed phenotype in P+ cells. Clonally derived P+ and P- recipient cells transfected with a human c-jun expression construct and overexpressing c-jun protein were tested for progression by assaying for constitutive or inducible anchorage independent phenotype and nude-mouse tumorigenicity. Overexpression of c-jun did not produce progression in P- cells but did increase the probability of progression in P+ cells (two of five transfectant cell lines progressed to the tumor phenotype). In addition, c-jun overexpression did not increase AP-1 activity in any of the P-/c-jun transfectants or in the two of five P+/c-jun transfectants that acquired the transformed phenotype. The P+/c-jun transfectants that showed elevated AP-1 activity did not progress to the tumor phenotype, demonstrating that an increase in AP-1 activity is insufficient for this progression. Since P(+)-to-tumor phenotype progression occurred in cells overexpressing c-jun but not AP-1, we propose that P(+)-to-transformed phenotype progression is c-jun dependent and AP-1 independent.
authors.affiliation: Laboratory of Viral Carcinogenesis, NCI, FCRDC, Frederick, MD 21702, USA.
authors.forename: R G
authors.initials: RG
authors.lastname: Watts
authors.forename: E T
authors.initials: ET
authors.lastname: Ben-Ari
authors.forename: L R
authors.initials: LR
authors.lastname: Bernstein
authors.forename: M J
authors.initials: MJ
authors.lastname: Birrer
authors.forename: D
authors.initials: D
authors.lastname: Winterstein
authors.forename: E
authors.initials: E
authors.lastname: Wendel
authors.forename: N H
authors.initials: NH
authors.lastname: Colburn
mesh_terms: D000818:Animals; D002455:Cell Division / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics*; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D016758:Genes, jun / Q000187:drug effects*; D006801:Humans; D051379:Mice; D010641:Phenotype; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012680:Sensitivity and Specificity; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics; D012879:Skin Physiological Phenomena; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism; D014162:Transfection
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D013755:Tetradecanoylphorbol Acetate