James Wise

Mentor

Aikseng Ooi, PhD

Department

Pharmacology and Toxicology

Abstract

Arsenic-induced NRF2 Expression: A role for TRIM Family Proteins
In the southwestern United States, metal contamination of water and soil has led to chronic exposure of communities to metal mixtures. This chronic exposure poses a major health problem and is associated with increased risk of disease development (e.g. cancer and type II diabetes). The Agency for Toxic Substances Disease Registry reports the number one contaminant at these sites is arsenic. While, the adverse health effects associated with arsenic exposure are known, the underlying mechanisms of arsenic-associated disease pathogenesis are unclear. Work in our laboratory has shown that prolonged arsenic exposure results in inhibition of the autophagy-lysosome pathway, resulting in prolonged activation of the critical antioxidant transcription factor NRF2. The superfamily of tripartite motif-containing (TRIM) proteins contains many members of TRIM proteins that have been linked to diseased states. Specifically, TRIM19 and TRIM29 have been linked to either NRF2 activation or degradation. TRIM19 has been linked to the degradation of NRF2 within the nucleus and TRIM29 has been proposed to lead to prolonged NRF2 activation. Thus, arsenic exposure may downregulate TRIM19 and activate TRIM29, leading to prolonged NRF2 activation and disease progression. The aim of our project is to understand how arsenic exposure may influence TRIM proteins leading to increased NRF2 activation. Since, arsenic contaminated soil and water increases disease prevalence in at risk human populations, the effects of arsenic on the molecular, cellular, and pathophysiologic alterations that contribute to disease progression will be extremely valuable in the generation of preventive and therapeutic strategies.