Transient cerebral ischemia activates processing of xbp1 messenger RNA indicative of endoplasmic reticulum stress.
Cells respond to conditions associated with endoplasmic reticulum (ER) dysfunction with activation of the unfolded protein response, characterized by a shutdown of translation and induction of the expression of genes coding for ER stress proteins. The genetic response is based on IRE1-induced processing of xbp1 messenger RNA (mRNA), resulting in synthesis of new XBP1proc protein that functions as a potent transcription factor for ER stress genes. xbp1 processing in models of transient global and focal cerebral ischemia was studied. A marked increase in processed xbp1 mRNA levels during reperfusion was observed, most pronounced (about 35-fold) after 1-h occlusion of the right middle cerebral artery. The rise in processed xbp1 mRNA was not paralleled by a similar increase in XBP1proc protein levels because transient ischemia induces severe suppression of translation. As a result, mRNA levels of genes coding for ER stress proteins were only slightly increased, whereas mRNA levels of heat-shock protein 70 rose about 550-fold. Under conditions associated with ER dysfunction, cells require activation of the entire ER stress-induced signal transduction pathway, to cope with this severe form of stress. After transient cerebral ischemia, however, the block of translation may prevent synthesis of new XBP1proc protein and thus hinder recovery from ischemia-induced ER dysfunction.
Paschen
Wulf
W
Department of Experimental Neurology, Max-Planck-Institute for Neurological Research, Gleuelerstr. 50, 50931 Köln, Germany. paschen@mpin-koeln.mpg.de
Aufenberg
Christoph
C
Hotop
Svenja
S
Mengesdorf
Thorsten
T
D000818:Animals; D001483:Base Sequence; D015415:Biomarkers; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000502:physiology*; D018869:Heat-Shock Response / Q000502:physiology; D002546:Ischemic Attack, Transient / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics*; D000071717:X-Box Binding Protein 1
D015415:Biomarkers; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C000605545:Xbp1 protein, rat; D000252:Calcium-Transporting ATPases