期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 27, 页码 12317-12322出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1007088107
关键词
excitotoxicity; kainic acid; oxidative stress
资金
- Alexander S. Onassis Public Benefit Foundation
- Swedish Research Council
- Knut and Alice Wallenberg Foundation
- Swedish Agency for Innovation Systems (VINNOVA)
- National Institutes of Health
- National Heart, Lung, and Blood Institute [R01 HL085593]
Induced expression of neuroprotective genes is essential for maintaining neuronal integrity after stressful insults to the brain. Here we show that NR4A nuclear orphan receptors are induced after excitotoxic and oxidative stress in neurons, up-regulate neuroprotective genes, and increase neuronal survival. Moreover, we show that NR4A proteins are induced by cAMP response element binding protein (CREB) in neurons exposed to stressful insults and that they function as mediators of CREB-induced neuronal survival. Animals with null mutations in three of six NR4A alleles show increased oxidative damage, blunted induction of neuroprotective genes, and increased vulnerability in the hippocampus after treatment with kainic acid. We also demonstrate that NR4A and the transcriptional coactivator PGC-1 alpha independently regulate distinct CREB-dependent neuroprotective gene programs. These data identify NR4A nuclear orphan receptors as essential mediators of neuroprotection after exposure to neuropathological stress.
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