Keap1/Nrf2 system regulates neuronal survival as revealed through study of keap1 gene-knockout mice.
Keap1 is proposed to be a sensor protein of electrophilic compounds and a transducer of the signal from electrophilic compounds for transcriptional activation. Thus, the use of keap1 gene-knockout (KO) mice is a straightforward approach in order to clarify the molecular background for the use of electrophilies as neuroprotective compounds. In the present report, we investigated the question as to how the deletion of the keap1 gene affects the activities of Nrf2 and survival of immature cortical neurons. In cortical cultures prepared from wild-type (WT) mice, Keap1 was expressed in the neurons, and Nrf2 protein was retained in their cytoplasm; whereas Nrf2 was translocated into the nuclei of neurons and phase 2 enzymes were constitutively activated in the cortical cultures from KO mice. Consistent with these results, cortical neurons from KO mice showed increased resistance to oxidative stress induced by high concentrations of glutamate and rotenone. These results suggest that the absence of Keap1 constitutively activates Nrf2, which then induces the phase 2 enzymes in neurons and induces increased resistance of cortical neurons to oxidative stress. This report is the first report to show that Keap1 is a key regulator of cell defense mechanisms of CNS neurons against oxidative stress.
Satoh
Takumi
T
Department of Welfare Engineering, Faculty of Engineering, Iwate University, Ueda 4-3-5, Morioka, Iwate 020-8551, Japan. tsatoh@iwate-u.ac.jp
Harada
Nobuhiko
N
Hosoya
Tomonori
T
Tohyama
Koujiro
K
Yamamoto
Masayuki
M
Itoh
Ken
K
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid / Q000494:pharmacology; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress; D021381:Protein Transport; D012402:Rotenone / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012402:Rotenone; D018698:Glutamic Acid