Abstract
Nrf2 is the pre-dominant transcription activator responsible for coordinated up-regulation of ARE-driven antioxidant and detoxification genes. The activity of Nrf2 is tightly regulated at basal levels through its ubiquitination by Cul3-Keap1 and consequential degradation. Upon exposure to stress, the Cul3-Keap1 ligase is inhibited, leading to Nrf2 stabilization and activation. Here we describe CACUL1/CAC1 as a positive regulator of the Nrf2 pathway. We found that CACUL1 is up-regulated by Nrf2-activating oxidative stresses in cells and in mice. The association of CACUL1 with the Cul3-Keap1 complex led to a decrease in Nrf2 ubiquitination levels at non-stressed as well as stressed conditions, and sensitized cells for higher Nrf2 activation. Furthermore, CACUL1 knock-down led to a decrease in Nrf2 activity and cell viability under stress. Our results show that CACUL1 is a regulator of Nrf2 ubiquitination, adding another regulatory layer to the Nrf2 antioxidant stress response.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Butylated Hydroxyanisole / pharmacology
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism
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Cell Survival / drug effects
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Cullin Proteins / antagonists & inhibitors
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Cullin Proteins / genetics*
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Cullin Proteins / metabolism
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Cytoskeletal Proteins / genetics*
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Cytoskeletal Proteins / metabolism
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Female
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Gene Expression Regulation
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HEK293 Cells
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HeLa Cells
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Heme Oxygenase-1 / genetics
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Heme Oxygenase-1 / metabolism
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Humans
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Kelch-Like ECH-Associated Protein 1
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Kidney / cytology
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Kidney / drug effects
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Kidney / metabolism*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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NAD(P)H Dehydrogenase (Quinone) / genetics
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NAD(P)H Dehydrogenase (Quinone) / metabolism
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NF-E2-Related Factor 2 / genetics*
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NF-E2-Related Factor 2 / metabolism
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Oxidants / pharmacology
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Oxidative Stress / genetics*
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Proteolysis
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction
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Ubiquitination
Substances
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Adaptor Proteins, Signal Transducing
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CACUL1 protein, mouse
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Carrier Proteins
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Cul3 protein, mouse
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Cullin Proteins
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Cytoskeletal Proteins
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Keap1 protein, mouse
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Kelch-Like ECH-Associated Protein 1
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Membrane Proteins
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NF-E2-Related Factor 2
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Nfe2l2 protein, mouse
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Oxidants
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RNA, Small Interfering
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Butylated Hydroxyanisole
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Heme Oxygenase-1
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Hmox1 protein, mouse
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NAD(P)H Dehydrogenase (Quinone)
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Nqo1 protein, mouse