Arsenic and its arsenical derivatives are estimated to effect greater than 200 million people worldwide. Exposure to arsenicals comes from a number of sources such as contaminated drinking water, soil or as an airborne pollutant. Various epidemiological studies have linked chronic arsenic exposure to a number of disease states including cancer of the lungs, bladder, or skin; metabolic diseases such as diabetes; cardiovascular and other vascular diseases; and skin problems such as 'black foot disease'. In addition to the epidemiological studies there has been a great deal of effort to understand the mechanisms of pathology, but to date many questions along these lines remain obfuscated. Part of the problem with understanding arsenic toxicity is the sheer number of cellular systems that arsenic alters. For instance arsenic leads to oxidative stress, compromise of protein quality control, heat-shock response, and cell-cycle alterations to name a few. Work from our lab has identified a crucial link in the effects of arsenic on cells. Chronic treatment with low levels of arsenite (one of the oxides of arsenic) leads to a compromise of autophagy, a major protein quality control pathway. This breach comes at the step of autophagosome/lysosome fusion, leading to a build-up of autophagosomes and high levels of the autophagy specificity factor, p62. Critically, p62 contains a recognition element for Keap1, which is a substrate recognition factor in the Cul3-Keap1-Rbx1 E3 ubiquitin ligase complex. This E3 complex normally maintains a low level of the oxidative stress responsive transcription factor, Nrf2. In the presence of excess p62, Keap1 is occupied, allowing for constitutive, high level expression of Nrf2 and subsequent activation of antioxidant response element regulated genes. This high-level expression confers a growth advantage on the cells and can lead to diseases such as cancer. Despite these mechanistic leaps, it remains the mechanism by which arsenite interferes with autophagy is unknown. In the present research program we propose the hypothesis that arsenicals interfere with the AAA+ protein quality control machine, p97. This provides a critical link between arsenic and autophagy as well as other protein quality control mechanisms. To probe the detailed mechanistic underpinnings of this arsenic-mediated breach we will use an array of detailed mechanistic enzymology studies, coupled with cellular biochemistry, and in vivo studies. These efforts will be greatly aided by the multi-PI team we have assembled.

Public Health Relevance

Arsenic and its arsenical derivatives pose a major health risk to large swaths of society from drinking water contamination, soil contamination, and as an airborne pollutant. Understanding the mechanism of progression from exposure to arsenicals to the ultimate pathological states that obtain is critical to treating or reversing these illnesses. he proposed studies will investigate the interplay between arsenic, autophagy, oxidative stress, and Nrf2 activation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES023758-05
Application #
9379459
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Reinlib, Leslie J
Project Start
2014-02-01
Project End
2018-10-31
Budget Start
2017-11-01
Budget End
2018-10-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Arizona
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Dodson, Matthew; Zhang, Donna D (2017) Non-canonical activation of NRF2: New insights and its relevance to disease. Curr Pathobiol Rep 5:171-176
Tao, Shasha; Liu, Pengfei; Luo, Gang et al. (2017) p97 Negatively Regulates NRF2 by Extracting Ubiquitylated NRF2 from the KEAP1-CUL3 E3 Complex. Mol Cell Biol 37:
Tillotson, Joseph; Zerio, Christopher J; Harder, Bryan et al. (2017) Arsenic Compromises Both p97 and Proteasome Functions. Chem Res Toxicol 30:1508-1514
Lee, Taehyung C; Kang, Minjin; Kim, Chan Hyuk et al. (2016) Dual Unnatural Amino Acid Incorporation and Click-Chemistry Labeling to Enable Single-Molecule FRET Studies of p97 Folding. Chembiochem 17:981-4
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de la Vega, Montserrat Rojo; Dodson, Matthew; Gross, Christine et al. (2016) Role of Nrf2 and Autophagy in Acute Lung Injury. Curr Pharmacol Rep 2:91-101
de la Vega, Montserrat Rojo; Dodson, Matthew; Chapman, Eli et al. (2016) NRF2-targeted therapeutics: New targets and modes of NRF2 regulation. Curr Opin Toxicol 1:62-70
Tillotson, Joseph; Bashyal, Bharat P; Kang, MinJin et al. (2016) Selective inhibition of p97 by chlorinated analogues of dehydrocurvularin. Org Biomol Chem 14:5918-21
Chapman, Eli; Maksim, Nick; de la Cruz, Fabian et al. (2015) Correction: Chapman, E.; et al. Inhibitors of the AAA+ chaperone p97. Molecules 2015, 20, 3027-3049. Molecules 20:4357-8
Tao, Shasha; Tillotson, Joseph; Wijeratne, E M Kithsiri et al. (2015) Withaferin A Analogs That Target the AAA+ Chaperone p97. ACS Chem Biol 10:1916-1924

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