Activation of p38 MAP kinase and ERK are required for ultraviolet-B induced c-fos gene expression in human keratinocytes

Abstract

The e ects of p38 MAP kinase and ERK on UVB induced c-fos gene expression were studied in a human keratinocyte cell line, FL30. UVB signi®cantly increased c-fos gene expression at both the transcriptional and protein levels. p38 and ERK were also signi®cantly activated after UVB irradiation. Treating the cells with p38 inhibitor SB202190 inhibited p38 activation, but not ERK; treating the cells with MEK-1 inhibitor PD98059 inhibited ERK activation without suppressing p38 activation. The kinase activation was determined by Western blots using phospho-p38 or ERK antibodies, or an in vivo p38 activity assay. Further studies demonstrated that blocking p38 almost completely abrogated UVB induced c-fos gene transcription and c-Fos protein synthesis. Inhibiting ERK partially abrogated UVB induced c-fos transcriptional and protein levels. Suppression of both p38 and ERK not only completely blocked UVB induced c-fos expression, but also decreased c-fos gene basal expression. Our data indicated that p38 may play a more important role than ERK in UVB induced cfos expression in human keratinocytes. Since c-fos expression may play an important role in UVB induced AP-1 activation, and AP-1 activation is known to play a role in tumor promotion, both p38 and ERK could be potential targets for chemoprevention of skin cancer.

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

“…UV-caused activation of MAPK family protein kinases, i.e., ERK, JNK, and p38, and their roles in cell cycle and apoptosis regulation as well as anti-apoptotic cell survival, signaling that influence overall UVB-induced tumorigenesis has been well studied in recent years by several laboratories (5,15,16). Based on these studies and our observations showing that tumors from silibinin treatment groups have decreased PCNA staining, together with an increased apoptotic cell population as well as strong levels of cleaved caspase-3, we next investigated the levels of phospho-and total ERK1/2, JNK1/2, and p38 kinase in tumors from UVB alone and silibinin-UVB-treated groups of mice.…”

Epidermal Growth Factor Receptor Signaling Is Partially Responsible for the Increased Matrix Metalloproteinase-1 Expression in Ocular Epithelial Cells after UVB Radiation

“…39 In this set of experiments, PECs were cultured under control conditions or irradiated and treated with either the ERK inhibitor (PD98059) or the JNK/p38 inhibitor (SB203580) for the times indicated, after which total RNA was extracted and analyzed by RT-PCR. Early (2 to 6 hours) and late (24 hours) time points of harvest were chosen because c-jun and c-fos are intermediate/early-induced genes whereas MMP-1 mRNA is induced later after UVB exposure 9 (Figure 4).…”

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

“…There are five isoforms of p38 MAPK, including a, h1, h2, g, and stress-activated protein kinase 4. MAPK signaling is stimulated by various stimuli, including growth factors, cytokines, and stressful stimuli, such as UVB (15,16). These kinases play an important role in the signaling events leading to proto-oncogene activation (15,16).…”

“…MAPK signaling is stimulated by various stimuli, including growth factors, cytokines, and stressful stimuli, such as UVB (15,16). These kinases play an important role in the signaling events leading to proto-oncogene activation (15,16). PI3K is a heterodimeric protein composed of a catalytic subunit (p110) and a regulatory subunit (p85), the signaling of which is frequently deregulated in carcinogenesis (17,18).…”