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Metals Induced Disruption of Ubiquitin Proteasome System, Activation of Stress Signaling and Apoptosis

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Cellular Effects of Heavy Metals

Abstract

The ubiquitin proteasomal system (UPS) is a highly conserved cellular pathway that plays an important role in the selective degradation of cellular proteins, helping to regulate a variety of vital cellular functions. Disruption of this system, therefore, can have significant downstream effects on critical cellular functions, impacting susceptibility and development of disease. Our research focuses on the identification and characterization of cellular responses to environmental metal exposure and the relationship to the development of neurodegenerative diseases . Our studies have shown that metals can also disrupt the UPS system and that some of these responses are mediated through key cell stress pathways in a similar fashion to what is seen with model UPS inhibitors . Although the accumulation of high molecular weight polyubiquitinated protein conjugates (HMW-polyUb) induced by metals was similar to what was seen with UPS inhibitor MG132, metals were less effective at inhibiting proteasomal activity, suggesting that the metals disrupt the UPS through an alternate mechanism. Our integrative analysis of genome-wide gene expression and pathway mapping in the mouse embryonic fibroblast cells (MEFs) exposed to cadmium (Cd), methyl mercury (MeHg), and arsenic (AS) demonstrated an induction of oxidative stress , disruption of UPS and cell cycle regulation . Cd and MeHg treatment in MEFs cells induced significant alteration of UPS pathway genes. Our findings strongly support the hypothesis that metal-induced disruption of UPS function results in changes in critical cellular mechanisms such as cell cycle regulation and apoptosis . This disruption has a significant implication for the potential development and susceptibility of neurodegenerative disease .

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Acknowledgements

This work was supported in part by the National Institute of Environmental Health Sciences (NIEHS), the Environmental Protection Agency (EPA), and the National Science Foundation (NSF) through the following grants: Toxicogenomics (NIEHS: U10 ES 11387 and R01-ES10613) the Center for Children’s Environmental Health Risks Research (NIEHS: 5-P01-ES009601 and EPA: RD-83170901), the Pacific Northwest Center for Human Health and Ocean Sciences (NIH/NIEHS: P50 ES012762 and NSF: OCE-0434087 and OCE-0910624) and the UW NIEHS Center for Ecogenetics and Environmental Health (NIEHS: 5 P30 ES07033). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS, NIH, NSF or EPA.

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  1. Department of Environmental Health, University of Washington, 4225 Roosevelt Way NE, Suite 100, 98105, Seattle, WA, USA

    Xiaozhong Yu, Rafael A. Ponce & Elaine M. Faustman

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  1. Xiaozhong Yu
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  2. Rafael A. Ponce
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  3. Elaine M. Faustman
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Correspondence to Elaine M. Faustman .

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  1. , Institute of Biology and Ecology, University of Debrecen, Egyetem Square 1, Debrecen, 4010, Hungary

    Gaspar Banfalvi

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Yu, X., Ponce, R.A., Faustman, E.M. (2011). Metals Induced Disruption of Ubiquitin Proteasome System, Activation of Stress Signaling and Apoptosis. In: Banfalvi, G. (eds) Cellular Effects of Heavy Metals. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-0428-2_14

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