ZEB1 links p63 and p73 in a novel neuronal survival pathway rapidly induced in response to cortical ischemia.
BACKGROUND
Acute hypoxic/ischemic insults to the forebrain, often resulting in significant cellular loss of the cortical parenchyma, are a major cause of debilitating injury in the industrialized world. A clearer understanding of the pro-death/pro-survival signaling pathways and their downstream targets is critical to the development of therapeutic interventions to mitigate permanent neurological damage.


RESULTS
We demonstrate here that the transcriptional repressor ZEB1, thought to be involved in regulating the timing and spatial boundaries of basic-Helix-Loop-Helix transactivator-mediated neurogenic determination/differentiation programs, functions to link a pro-survival transcriptional cascade rapidly induced in cortical neurons in response to experimentally induced ischemia. Employing histological, tissue culture, and molecular biological read-outs, we show that this novel pro-survival response, initiated through the rapid induction of p63, is mediated ultimately by the transcriptional repression of a pro-apoptotic isoform of p73 by ZEB1. We show further that this phylogenetically conserved pathway is induced as well in the human cortex subjected to episodes of clinically relevant stroke.


CONCLUSIONS
The data presented here provide the first evidence that ZEB1 induction is part of a protective response by neurons to ischemia. The stroke-induced increase in ZEB1 mRNA and protein levels in cortical neurons is both developmentally and phylogenetically conserved and may therefore be part of a fundamental cellular response to this insult. Beyond the context of stroke, the finding that ZEB1 is regulated by a member of the p53 family has implications for cell survival in other tissue and cellular environments subjected to ischemia, such as the myocardium and, in particular, tumor masses.
Bui
Thai
T
Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Sequeira
Judith
J
Wen
Tong Chun
TC
Sola
Augusto
A
Higashi
Yujiro
Y
Kondoh
Hisato
H
Genetta
Tom
T
D000818:Animals; D001483:Base Sequence; D002545:Brain Ischemia / Q000139:chemically induced / Q000473:pathology*; D016923:Cell Death; D015687:Cell Hypoxia; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005947:Glucose / Q000172:deficiency; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology*; D009687:Nuclear Proteins / Q000378:metabolism*; D010100:Oxygen; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D020521:Stroke / Q000139:chemically induced; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation; D000071799:Zinc Finger E-box-Binding Homeobox 1
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D020033:Protein Isoforms; C000606460:TP73 protein, human; D014157:Transcription Factors; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C486307:ZEB1 protein, human; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1; D005947:Glucose; D010100:Oxygen