Superfund Research Program
Arsenic and the Ubiquitin-Lysosome Pathway
Project Leader: Bruce A. Stanton
Grant Number: P42ES007373
Funding Period: 2005-2020
Project Summary (2008-2014)
The long-term objective of this research is to elucidate the cellular and molecular mechanisms whereby arsenic, a toxic metalloid, increases the incidence of cancer, atherosclerotic and cardiovascular disease, reproductive and developmental problems, and type 2 diabetes mellitus.
The overarching hypothesis is that very low, environmentally relevant levels of arsenic dysregulates the expression of the serum glucocorticoid kinase (SGK1), which is over-expressed in many cancers, most notably breast cancer. Moreover, dysregulation of SGK1 has also been implicated in Parkinson's Disease, Huntington's Disease, diabetes, hypertension, and obesity.
In preliminary studies, scientists made the novel observation that arsenic reduces SGK1 expression and, thereby, activates the ubiquitin-lysosomal mediated degradation of the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride ion channel that regulates salt homeostasis in euryhaline teleosts (e.g., salmon and killifish), and human airway epithelia cells. In this study, project scientists are focusing on elucidating the cellular and molecular mechanisms whereby arsenic dysregulates the expression and function of SGK1 and CFTR. In particular, studies are being conducted to test the hypothesis that arsenic is an endocrine disrupter and inhibits the transcriptional activation of SGK1 by disrupting cortisol-glucocorticoid receptor signaling. In addition, studies are also being conducted to elucidate how SGK1 regulates the ubiquitin-lysosomal pathway. Accordingly, studies are beingconducted to test the hypothesis that SGK1 down-regulates the ubiquitin-lysosomal pathway by inhibiting Nedd 4-2, a ubiquitin E3 ligase that selectively ubiquitinates proteins, such as CFTR, and targets them for degradation in the lysosome.
The studies use three model systems: Fundulus heteroclitus (killifish), an environmental sentinel organism; Xenopus oocytes, a model system used extensively to study the regulation of ion channels, including CFTR; and polarized human airway epithelial cells (CFBE). These studies are significantly increasing the understanding of the molecular mechanisms whereby very low levels of arsenic disrupt SGK1 gene expression, function, and the ubiquitin-lysosomal pathway, as well as elucidating the cell and molecular mechanisms whereby arsenic and SGK1 may contribute to breast cancer, Parkinson's Disease, Huntington's Disease, type 2 diabetes, hypertension, and obesity.