QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, May 27, 2009, 29(21):7003-7014; doi:10.1523/JNEUROSCI.1110-09.2009

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Jung, J. E. Articles by Chan, P. H. PubMed PubMed Citation Articles by Jung, J. E. Articles by Chan, P. H.

 Previous Article  |  Next Article 

Neurobiology of Disease
Regulation of Mn-Superoxide Dismutase Activity and Neuroprotection by STAT3 in Mice after Cerebral Ischemia

Joo Eun Jung,^1,2,3 * Gab Seok Kim,^1,2,3 * Purnima Narasimhan,^1,2,3 Yun Seon Song,^1,2,3 and Pak H. Chan^1,2,3

¹Departments of Neurosurgery and ²Neurology and Neurological Sciences, and ³Program in Neurosciences, Stanford University School of Medicine, Stanford, California 94305

Correspondence should be addressed to Pak H. Chan, Neurosurgical Laboratories, Stanford University, 1201 Welch Road, MSLS #P314, Stanford, CA 94305-5487. Email: phchan{at}stanford.edu

Cerebral ischemia and reperfusion increase superoxide anions (O₂^·–) in brain mitochondria. Manganese superoxide dismutase (Mn-SOD; SOD2), a primary mitochondrial antioxidant enzyme, scavenges superoxide radicals and its overexpression provides neuroprotection. However, the regulatory mechanism of Mn-SOD expression during cerebral ischemia and reperfusion is still unclear. In this study, we identified the signal transducer and activator of transcription 3 (STAT3) as a transcription factor of the mouse Mn-SOD gene, and elucidated the mechanism of O₂^·– overproduction after transient focal cerebral ischemia (tFCI). We found that Mn-SOD expression is significantly reduced by reperfusion in the cerebral ischemic brain. We also found that activated STAT3 is usually recruited into the mouse Mn-SOD promoter and upregulates transcription of the mouse Mn-SOD gene in the normal brain. However, at early postreperfusion periods after tFCI, STAT3 was rapidly downregulated, and its recruitment into the Mn-SOD promoter was completely blocked. In addition, transcriptional activity of the mouse Mn-SOD gene was significantly reduced by STAT3 inhibition in primary cortical neurons. Moreover, we found that STAT3 deactivated by reperfusion induces accumulation of O₂^·– in mitochondria. The loss of STAT3 activity induced neuronal cell death by reducing Mn-SOD expression. Using SOD2–/+ heterozygous knock-out mice, we found that Mn-SOD is a direct target of STAT3 in reperfusion-induced neuronal cell death. Our study demonstrates that STAT3 is a novel transcription factor of the mouse Mn-SOD gene and plays a crucial role as a neuroprotectant in regulating levels of reactive oxygen species in the mouse brain.

---

Received March 6, 2009; revised April 10, 2009; accepted April 29, 2009.

Correspondence should be addressed to Pak H. Chan, Neurosurgical Laboratories, Stanford University, 1201 Welch Road, MSLS #P314, Stanford, CA 94305-5487. Email: phchan{at}stanford.edu

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help