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Published on: June 7, 2019
Cross-validation of murine UV signal transduction pathways in human skin
Janine G Einspahr1, G Timothy Bowden, David S Alberts
1Department of Medicine, University of Arizona, Tucson, AZ, USA. jeinspahr@azcc.arizona.edu
Abstract:
Acute UVB irradiation of mouse skin results in activation of phospatidyinositol-3 (PI-3) kinase and mitogen-activated protein kinase (MAPK) pathways leading to altered protein phosphorylation and downstream transcription of genes. We determined whether activation of these pathways also occurs in human skin exposed to 4x minimal erythemic dose of UVB in 23 volunteers. Biopsies were taken prior to, at 30 min, 1 and 24 h post-UVB. In agreement with mouse studies, the earliest UV-induced changes in epidermis were seen in phospho-CREB (two- and five-fold at 30 min and 1 h) and in phospho-MAPKAPK-2 (three-fold at both 30 min and 1 h). At 1 h, phospho-c-JUN and phospho-p38 were increased five- and two-fold, respectively. Moreover, phospho-c-JUN and phospho-p38 were further increased at 24 h (12- and six-fold, respectively). Phospho-GSK-3beta was similarly increased at all time points. Increases in phospho-p53 (12-fold), COX-2 (four-fold), c-FOS (14-fold) and apoptosis were not seen until 24 h. Our data suggest that UVB acts through MAPK p38 and PI-3 kinase with phosphorylation of MAPKAPK-2, CREB, c-JUN, p38, GSK-3beta and p53 leading to marked increases in c-FOS, COX-2 and apoptosis. Validation of murine models in human skin will aid in development of effective skin cancer chemoprevention and prevention strategies.
Insights
UVB exposure activates key signaling pathways in human skin, including the PI-3 and MAPK pathways. These activations lead to increased protein phosphorylation and downstream gene transcription, impacting skin cell responses and potentially aiding skin cancer prevention.
Area of Science:
- Dermatology
- Molecular Biology
- Biochemistry
Background:
- Ultraviolet B (UVB) radiation is a known carcinogen that induces DNA damage and cellular responses in the skin.
- Murine models show UVB activates phosphatidylinositol-3 (PI-3) kinase and mitogen-activated protein kinase (MAPK) pathways, leading to altered gene transcription.
Purpose of the Study:
- To investigate if similar PI-3 and MAPK pathway activations occur in human skin following UVB exposure.
- To correlate early molecular events with later cellular responses like apoptosis and gene expression.
Main Methods:
- Human skin biopsies from 23 volunteers were collected before and at 30 minutes, 1 hour, and 24 hours after exposure to 4x minimal erythemic dose of UVB.
- Protein phosphorylation levels of key signaling molecules (CREB, MAPKAPK-2, c-JUN, p38, GSK-3beta, p53) and expression of COX-2 and c-FOS were analyzed using Western blotting or similar techniques.
- Apoptosis was assessed at different time points post-UVB exposure.
Main Results:
- UVB rapidly induced phosphorylation of CREB and MAPKAPK-2 within 30 minutes to 1 hour.
- Phosphorylation of c-JUN and p38 increased by 1 hour and significantly elevated by 24 hours post-UVB.
- Increased phosphorylation of p53, COX-2, c-FOS, and apoptosis were observed at 24 hours, indicating delayed but substantial cellular responses.
Conclusions:
- UVB exposure in human skin activates PI-3 and MAPK pathways, mirroring findings in murine models.
- The sequential activation of signaling molecules (CREB, c-JUN, p38, p53) and downstream targets (c-FOS, COX-2) culminates in apoptosis.
- Validating murine models with human skin data is crucial for developing effective skin cancer chemoprevention strategies.
