Low-level arsenite causes accumulation of ubiquitinated proteins in rabbit renal cortical slices and HEK293 cells

Arsenic is a known human carcinogen that affects a variety of processes within the cell. In this study, the effects of environmentally relevant As(III) exposures on the ubiquitin (Ub)-proteasome pathway have been investigated. Low-level As(III) exposure (0.5 - 10 muM) causes an accumulation of high-molecular-weight ubiquitin protein conjugates in both precision-cut rabbit renal-cortical slices and human embryonic kidney (HEK) 293 cells. The As(III) doses that induced these molecular changes were subeytotoxic in both model systems. Doses of 10 muM As(III) decreased cellular activity of the 20S proteasome by 40 and 15% in slices and HEK293 cells, respectively. As(III) did not cause any notable difference in Ub-conjugating activity of rabbit renal slices or HEK293 cells. Since ubiquitination plays such a vital role in maintaining cellular homeostasis, this noticeable perturbation of cellular ubiquitination is likely to have a multitude of signaling effects within the cells and may contribute to the pathogenesis of low-level arsenic. (C) 2003 Elsevier Science (USA). All rights reserved.