Abstract
The relationship between cell transformation and p38 MAP kinase, a major mitogen-activated protein (MAP) kinase pathway converting signals of various extracellular stimuli into expression of specific target genes through activation of transcription factors, still remains unclear. The aim of the present study was to investigate the role of the p38 MAP kinase pathway in epidermal growth factor (EGF)-induced cell transformation in JB6 cells. Our data show that a dominant negative mutant of p38 MAP (DN-p38) kinase inhibits EGF-promoted JB6 Cl41 cell transformation and that SB202190, an inhibitor of p38 MAP kinase, also inhibits JB6 Cl41 cell transformation in a dose-dependent manner. Moreover, our results show that DN-p38 MAP kinase inhibits the phosphorylation of EGF-stimulated activating transcription factor-2 (ATF-2) and signal transducer and activator of transcription 1 (STAT1). Additionally, DN-p38 MAP kinase inhibits EGF-induced phosphorylation of c-Myc (Thr58/Ser62). Gel shift assays indicate that DN-p38 MAP kinase inhibits EGF-induced activator protein-1 (AP-1) DNA binding in a dose-dependent manner. These results show that p38 MAP kinase plays a key role in the regulation of EGF-induced cell transformation in JB6 cells through regulation of phosphorylation of p38 MAP kinase and activation of its target genes in phosphorylation, c-Myc cell transformation-related genes, and AP-1 binding ability.
Highlights
On the other hand, extracellular signal-regulated kinases (ERKs) are predominantly activated by mitogenic stimuli, including mitogens and growth factors, and activated ERKs are involved in cell differentiation and development [2, 3]
activator protein-1 (AP-1) activation is involved in JB6 cell transformation promoted by epidermal growth factor (EGF) and the phorbol ester 12-Otetradecanoyl-phorbol-13-acetate (TPA) [10, 11]
The results obtained show that p38 mitogen-activated protein (MAP) kinase plays a critical role in regulation of JB6 Cl41 cell transformation promoted by EGF through the inhibition of the phosphorylation of activating transcription factor-2 (ATF-2), signal transducer and activator of transcription 1 (STAT1), and c-Myc and the repression of AP-1 binding ability
Summary
ERKs are predominantly activated by mitogenic stimuli, including mitogens and growth factors, and activated ERKs are involved in cell differentiation and development [2, 3]. One major function of the p38 kinase and JNKs pathways is regulation of inflammation and apoptosis, in many cases the biological consequences of p38 kinase and JNK activation overlap with those of ERKs in mediation of cell growth and differentiation [2, 3, 6, 7]. We studied ERKs regulation of epidermal growth factor (EGF)-induced cell transformation in promotion sensitive (Pϩ) derivatives of the mouse epidermal JB6 cell line [8]. Gel shift assays indicate that DN-p38 MAP kinase inhibits EGF-induced activator protein-1 (AP-1) DNA binding in a dose-dependent manner. These results show that p38 MAP kinase plays a key role in the regulation of EGF-induced cell transformation in JB6 cells through regulation of phosphorylation of p38 MAP kinase and activation of its target genes in phosphoryla-
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