Role of p38 mitogen-activated protein kinases in ultraviolet-B irradiation-induced activator protein 1 activation in human keratinocytes

Abstract

The effects of p38 mitogen‐activated protein kinases on ultraviolet (UV) B irradiation–induced activator protein 1 (AP‐1) activation were studied in a human keratinocyte cell line, HaCaT. The HaCaT cells were stably transfected with a plasmid containing a promoter fragment of human collagenase 1 driving a luciferase reporter gene. There is an AP‐1–binding site within this fragment, without any other known transcription factor–binding sites. As we reported previously, UVB significantly induces activation of AP‐1 and p38 in HaCaT cells. SB202190, a p38‐specific inhibitor, inhibits UVB‐induced p38 activation and c‐fos gene expression. In the present study, we further examined the role of p38 in UVB‐induced AP‐1 activation. We observed that SB202190 strongly inhibited UVB‐induced AP‐1 transactivation at different time points and UVB doses in transfected HaCaT cells. Furthermore, SB202190 markedly inhibited UVB‐induced AP‐1 DNA binding as determined by mobility shift analyses. These results suggested, for the first time, that activation of p38 is required for UVB‐induced AP‐1 activation in human keratinocytes. In addition, a potential mechanism of UVB‐induced AP‐1 activation through p38 is to enhance AP‐1 complex binding to its target DNA. Because c‐fos gene expression plays a critical role in UVB‐induced AP‐1 activation and p38 is required for UVB‐induced c‐fos gene expression in HaCaT cells, as reported previously, a potential UVB signaling cascade for AP‐1 activation in human keratinocytes has been determined. This cascade involves UVB, p38 activation, c‐fos gene expression, and AP‐1 activation. Mol. Carcinog. 28:196–202, 2000. © 2000 Wiley‐Liss, Inc.

Silibinin Protects against Photocarcinogenesis via Modulation of Cell Cycle Regulators, Mitogen-Activated Protein Kinases, and Akt Signaling

“…P38 mediates UVB apoptosis by inducing cytochrome c release into cytosol followed by caspase-3 activation in HaCaT cells (39). Conversely, UVB-caused induction of p38 activity followed by activation of transcription factor AP-1 is also reported in HaCaT human keratinocytes, which could lead to pro-survival/anti-apoptotic response (40). Consistent with these reports, silibinin treatments in UVB tumorigenesis studies resulted in a strong increase in ERK1/2, JNK1/2, and p38 phosphorylation in tumor samples, suggesting their possible involvement in an overall silibinin efficacy in causing apoptosis induction in tumor cells.…”

Molecular basis of parthenolide-dependent proapoptotic activity in cancer cells.

“…It is rather controversial in regard to the exact role of JNK in UV-mediated apoptosis. For instance, JNK has been shown to be required for UVinduced apoptotic cell death in mouse embryonic fibroblast [50], while others demonstrated the antiapoptotic role of JNK in UV-induced apoptosis [51].…”

Inhibition of p38 Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase Decreases UVB-Induced Activator Protein-1 and Cyclooxygenase-2 in a SKH-1 Hairless Mouse Model

“…SB202190 and LY294002 were used in these studies to implicate p38 MAPK and PI3K in UVB-induced AP-1 activation and COX-2 expression in vivo. Our laboratory has reported previously that UVB mediates increases in AP-1 activation and COX-2 through p38 MAPK and PI3K in the human keratinocyte cell line, HaCaT (16,(32)(33)(34). Therefore, we wanted to extend these studies into an in vivo system to specifically validate p38 MAPK and PI3K as potential molecular targets for the chemoprevention of NMSC.…”