Role of Protein Phosphorylation in the Regulation of NF-E2–Related Factor 2 Activity
Autor: | Hsueh-Cheng Huang, Philip J. Sherratt, Truyen Nguyen, Cecil B. Pickett |
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Rok vydání: | 2004 |
Předmět: | |
DOI: | 10.1016/s0076-6879(04)78022-2 |
Popis: | Publisher Summary The antioxidant response element (ARE) is a cis-acting enhancer that coordinates the induction of a battery of genes in response to oxidative stress and electrophilic compounds. These genes contain the consensus ARE sequence within their promoter region and encode phase II detoxification enzymes or antioxidant proteins. A number of mechanisms are proposed that may contribute to maintaining active nuclear Nrf2 in response to a toxic insult. One mechanism involves reactive oxygen species (ROS) and electrophiles directly modifying the sulfhydryl groups of cysteine residues on the Keap1 repressor protein. Subsequently, other signal transduction pathways have been implicated as having effects on the ARE, including phosphatidylinositol 3-kinase (PI3K) and protein kinase C (PKC) isoenzymes. It is clear that the activity of Nrf2 is regulated by at least two signaling pathways in hepatoma cells. The interaction between Nrf2 and the Keap1 repressor protein is affected by a direct action of PKC on the Nrf2 protein. Phosphorylation of the transcription factor at serine 40 leads to a weaker interaction with the repressor. In addition, stabilization of the Nrf2 protein through a mechanism involving the MAPK cascade is also important for regulating transactivation of the ARE. Currently, it is not known whether a kinase in this cascade acts on Nrf2 directly or exerts its effects through targeting other components of the ARE pathway. |
Databáze: | OpenAIRE |
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