Shortage of Mitogen-Activated Protein Kinase Is Responsible For Resistance to Ap-1 Transactivation and Transformation in Mouse Jb6 Cells

The JB6 mouse epidermal cell system, which includes tumor promotion-sensitive (P+) and tumor promotion-resistant (P-) cells, is a well-established and extensively used cell culture model for studying the mechanism of late-stage tumor promotion, Tumor promoters, such as 12-O-tetradecanoylphorbol 13-acetate (TPA) or epidermal growth factor (EGF), induce high levels of activator protein 1 (AP-1) activity and large, tumorigenic, anchorage-independent colonies in soft agar at a high frequency in JB6 P+ cells, but not in JB6 P- cells, We report here a molecular explanation for the defect in the AP-1 activation and promotion-resistant phenotype of P- cells, We demonstrate that the lack of AP-1 activation and cell transformation responses to TPA and EGF in P- cells appears attributable to the low level of mitogen-activated protein kinase (MAPK) (extracellular signal-regulated protein kinase, Erk) in these cells, TPA and EGF induce transactivation of AP-1 activity in pf cells but not in P- cells, Nonphosphorylated forms and TPA- or EGF-induced phosphorylated forms of Erks (Erk1 and Erk2) in P- cells were much lower than those in P+ cells. Stable transfection of wild-type MAPK (Erk2) into P- cells restored its response to TPA and EGF for both AP-1 activation and cell transformation, These results suggest that the shortage of MAPK (Erk1 and Erk2) appears to be an important contributor to the tumor promotion-resistant phenotype in JB6 cells. [References: 40]

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