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Mitogen-activated Protein Kinase Signaling Alterations and Functional Consequences of Ultraviolet Irradiation and Arsenite in Human Keratinocytes

EPA Grant Number: F5D10633
Title: Mitogen-activated Protein Kinase Signaling Alterations and Functional Consequences of Ultraviolet Irradiation and Arsenite in Human Keratinocytes
Investigators: Cooper, Karen
Institution: University of New Mexico
EPA Project Officer: McClure, Karen
Project Period: August 21, 2005 through December 7, 2006
Project Amount: $83,395
RFA: STAR Graduate Fellowships (2005)
Research Category: Academic Fellowships

Description:

Objective:

The purpose of this project is to investigate the potential convergence of signaling pathways and synergistic upregulation of downstream target genes by UV irradiation and arsenite.

Approach:

The skin is a major target organ for both arsenic and ultraviolet irradiation. UV irradiation and arsenic are known to activate the epidermal growth factor (EGF) receptor and stimulate intracellular signaling cascades. These agents can also induce signaling via the stress-activated kinases without involvement of EGF receptor activity. In order to investigate the potential synergistic effects of arsenite and UV irradiation, dose response and time course experiments will be performed on cultured human keratinocytes; HaCat (spontaneously immortalized human keratinocytes) and normal human epidermal keratinocyte (NHEK) cell lines). Western analyses for proteins involved in mitogen-activated protein (MAP) kinase signaling cascades or downstream transcriptional targets will be performed. Pharmacological techniques will be employed to determine the relative contribution of EGF receptor-MAP kinase activation, stress-activated signaling and/or reactive oxygen species (ROS) generation in the induction of these proteins. Finally, in vitro wounding assays will show whether the described treatments aid or inhibit migratory ability of the treated cells. This method will also allow visual inspection of induced morphological changes.

Expected Results:

These experiments will show activation of MAP kinases and induction of downstream gene products in response to arsenite, UV, or both in combination. Pharmacological inhibition of MAP kinases and ROS will provide insight into the dominant pathways involved and required components. The in vitro wounding assays will provide evidence of further functional consequences following arsenite/UV-induction of the target genes.

Supplemental Keywords:

arsenic, ultraviolet irradiation, MAP kinase, reactive oxygen species, keratinocytes, , Scientific Discipline, Health, Risk Assessments, Health Risk Assessment, Ecological Risk Assessment, Biochemistry, arsenic, analysis of chemical exposure, exposure dose, UV radition, human health risk, biological assay, dose-response, epidermal growth factor, keratoses, human exposure, combination exposure

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The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.

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