The small GTP-binding protein Cdc42 is required for nerve growth factor withdrawal-induced neuronal death.
An increase in the level of the c-Jun transcription factor and of its phosphorylation has previously been shown to be essential for nerve growth factor (NGF) withdrawal-induced apoptosis of rat sympathetic neurons (SCG). The Rho-like GTPases Cdc42 and Rac1 are involved in the regulation of a number of cellular processes, including activation of the c-Jun NH2-terminal kinase (JNK) pathway. Therefore, we have investigated the role of these GTPases in this process. Overexpression of activated Rac1 or Cdc42 in SCG neurons maintained in the presence of NGF induced apoptosis, whereas expression of dominant negative mutants of Cdc42 or Rac1 blocked apoptosis following NGF withdrawal. Cdc42 activation produced an increase in the level of c-Jun and of its phosphorylation. Furthermore, Cdc42-induced death was prevented by coexpressing the c-Jun dominant negative FLAGDelta169. Thus, Cdc42 appears to function as an initiator of neuronal cell death by activating a transcriptional pathway regulated by c-Jun.
Bazenet
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Eisai London Research Laboratories, Bernard Katz Building, University College London, Gower Street, London WC1E 6BT, United Kingdom. cbazenet@elrl.co.uk
Mota
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Rubin
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005724:Ganglia / Q000378:metabolism / Q000473:pathology*; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein
D018797:Cell Cycle Proteins; D009414:Nerve Growth Factors; D011494:Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D019204:GTP-Binding Proteins; D020764:cdc42 GTP-Binding Protein