Oxidative-stress-induced alterations in Sp factors mediate transcriptional regulation of the NR1 subunit in hippocampus during hypoxia.
Ascent to high altitude is associated with tissue hypoxia resulting from the decrease in partial pressure of atmospheric oxygen. The hippocampus, in particular, is highly vulnerable to hypoxic insult, which at least in part can be attributed to the occurrence of glutamate excitotoxicity. Although this excitotoxic damage is often related to increased NMDA receptor activation and subsequent calcium-mediated free radical generation, the mechanisms involving the transcriptional regulation of NMDA receptor subunit expression by hypoxic stress remains to be explored. Our study reveals a novel mechanism for the regulation of expression of the NR1 subunit of NMDA receptors by the Sp family of transcription factors through an oxidative-stress-mediated mechanism that also involves the molecular chaperone Hsp90. The findings not only show the occurrence of lipid peroxidation and DNA damage in hippocampal cells exposed to hypoxia but also reveal a calcium-independent mechanism of selective oxidation and degradation of Sp3 by the 20S proteasome. This along with increased DNA binding activity of Sp1 leads to NR1 upregulation in the hippocampus during hypoxic stress. The study therefore provides evidence for free radical-mediated regulation of gene expression in hypoxia and the scope of the use of antioxidants in preventing excitotoxic neuronal damage during hypoxia.
Hota
Sunil Kumar
SK
Defence Institute of High Altitude Research, Leh, Ladakh, Jammu and Kashmir, India.
Hota
Kalpana Barhwal
KB
Prasad
Dipti
D
Ilavazhagan
Govindasamy
G
Singh
Shashi Bala
SB
D000578:Amidines / Q000008:administration & dosage; D000818:Animals; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D051705:Sp3 Transcription Factor / Q000235:genetics / Q000378:metabolism
D000578:Amidines; D018841:HSP90 Heat-Shock Proteins; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D016329:Sp1 Transcription Factor; C497123:Sp3 protein, rat; D051705:Sp3 Transcription Factor; C046728:2,2'-azobis(2-amidinopropane); D046988:Proteasome Endopeptidase Complex