p38 Mitogen-activated Protein Kinase Regulation of JB6 Cl41 Cell Transformation Promoted by Epidermal Growth Factor

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 The mitogen-activated protein kinases (MAPKs), 1 including p38 kinase, c-Jun NH 2 -terminal kinases (JNKs), extracellular signal-regulated kinases (ERKs), and signal transduction cascades, are vital mediators of many cellular functions such as growth, development, proliferation, differentiation, malignant transformation, inflammation, and apoptosis (1-3). p38 MAP kinase is activated by cellular stresses including inflammatory cytokines, ultraviolet light, and growth factors, and the activated p38 MAP kinase has been shown to phosphorylate several transcription factors including ATF-2, STAT1, the Max/ Myc complex, and myocyte enhancer factor 2 (MEF2) (1, 4 -6). On the other hand, ERKs are predominantly activated by mitogenic stimuli, including mitogens and growth factors, and activated ERKs are involved in cell differentiation and development (2, 3). Although 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).Previously, we studied ERKs regulation of epidermal growth factor (EGF)-induced cell transformation in promotion sensitive (P ϩ ) derivatives of the mouse epidermal JB6 cell line (8). Results showed that inhibition of ERKs appeared to be an important contributor to the tumor promotion-resistant phenotype in JB6 cells. A recent study showed that the p38 kinase and JNKs pathways cooperate to transactivate the vitamin D receptor through the c-Jun/activator protein-1 (AP-1) (9). This result indicates that a connection exists between p38 MAP kinase and AP-1. But AP-1 activation is involved in JB6 cell transformation promoted by EGF and the phorbol ester 12-Otetradecanoyl-phorbol-13-acetate (TPA) (10, 11). AP-1 is a dimeric complex consisting of proteins encoded by the jun and fos gene families, and the AP-1 binding region in these genes is referred to as the TPA response element (TRE). AP-1 induces the transcription of genes that are related to cell prol...

Mitogen- and Stress-Activated Kinase 1–Mediated Histone H3 Phosphorylation Is Crucial for Cell Transformation

“…MSK1 is a nuclear kinase that acts downstream of both the ERK and p38 MAPKs and has been suggested to be activated in response to EGF, TPA, UVB, and anisomycin (7,8,13,14). MSK1 phosphorylates various transcription factors, including CREB, 3 ) were exposed to TPA (20 ng/mL, top ) or EGF (10 ng/mL, bottom ) in 1 mL of 0.3% BME agar containing 10% FBS.…”

“…Recently, MSK1 was shown to play a positive role in the control of cell proliferation of HaCaT keratinocytes (11) and might play a role in pathogenesis of psoriasis by regulating the production of proinflammatory cytokines in psoriatic epidermis (12). MSK1 was suggested to be activated in response to tumor promoters, such as epidermal growth factor (EGF), 12-O-tetradecanoylphorbol-13-acetate (TPA), or UVB (7,13,14). However, the role of MSK1 in tumorigenesis or cell transformation is not completely clear.…”

Nitration of p38 MAPK in the placenta: association of nitration with reduced catalytic activity of p38 MAPK in pre-eclampsia

“…Higher levels of phospho-p38 activity were reflected in higher amounts of phospho-ATF-2. This is an assay widely used in measurement of p38 MAPK activity (Samet et al, 1998;He et al, 2003). It has also been demonstrated that inhibitors of p38 MAPK can inhibit phosphorylation of ATF-2 (Lewis et al, 2005).…”

Analysis of the role of p38 MAP kinase in epidermal growth factor-induced JB6 Cl41 cell transformation by cDNA array

“…Moreover, recent studies showed that p38 MAPK is also involved in cell transformation. Erdogan et al (2007) exploration illustrated that TC21-induced EpH4 cell transformation and proliferation required activation of p38 MAPK, and we found that p38 MAPK activity was necessary for EGF-induced JB6 Cl41 cell transformation in vitro (He et al, 2003).…”

“…MAP kinase cascades are known to play a considerable role in malignant transformation (Greenberg et al, 2002;Takenobu et al, 2003). Fortunately, we found that p38 MAP kinase is involved in epidermal growth factor (EGF)-induced JB6 Cl41 cells' transformation (He et al, 2003). However, the more detail information on p38 MAP kinase involved cell transformation is unknown.…”