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

Academic Article

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. © 1995 Wiley‐Liss, Inc. Copyright © 1995 Wiley‐Liss, Inc., A Wiley Company
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    Author List

  • Watts RG; Ben Ari ET; Bernstein LR; Birrer MJ; Winterstein D; Wendel E; Colburn NH
  • Start Page

  • 27
  • End Page

  • 36
  • Volume

  • 13
  • Issue

  • 1