Document Detail

Mechanisms of apoptosis in PC12 cells irreversibly differentiated with nerve growth factor and cyclic AMP.
MedLine Citation:
PMID:  10064788     Owner:  NLM     Status:  MEDLINE    
PC12 cells treated with cAMP become irreversibly differentiated and die by apoptosis when deprived of trophic support, instead of dedifferentiating and reentering the cell cycle. To approach the molecular mechanism underlying the cAMP-induced switch from differentiation/proliferation to apoptosis, we compared three sequential markers of a candidate apoptogenic signal transduction pathway (ceramide, free radicals and NF-kappaB), after trophic factor withdrawal in PC12 cells before and after irreversible differentiation. Serum withdrawal increased ceramide and free radical production regardless of the state of differentiation of the cells. It was followed by cell death, however, only in the absence of NGF and/or cAMP, and was no longer required for apoptosis in NGF/cAMP-differentiated cells. NGF and cAMP withdrawal sufficed. NF-kappaB was activated by NGF withdrawal in reversibly differentiated PC12 cells during dedifferentiation and reentry into the cell cycle, whereas in NGF/cAMP-differentiated cells, it was activated, at a late stage of the apoptotic process, concomitantly with cell death. These results show that a serum factor inhibits ceramide-dependent apoptosis upstream of ceramide and free radical production, whereas NGF- and cAMP-dependent mechanisms inhibit apoptosis either downstream or parallel to these events. After terminal differentiation by cAMP, apoptosis appears to be initiated from the second site, consistent with the serum independence of these cells and the absence of ceramide and free radical production when the NGF/cAMP-dependent inhibitions are released. The differential regulation of NF-kappaB appears to be an important step in the switch from mitosis to apoptosis that occurs during irreversible differentiation of PC12 cells by cAMP.
N Lambeng; P P Michel; B Brugg; Y Agid; M Ruberg
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Brain research     Volume:  821     ISSN:  0006-8993     ISO Abbreviation:  Brain Res.     Publication Date:  1999 Mar 
Date Detail:
Created Date:  1999-04-22     Completed Date:  1999-04-22     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  0045503     Medline TA:  Brain Res     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  60-8     Citation Subset:  IM    
Copyright Information:
Copyright 1999 Elsevier Science B.V.
INSERM U.289, Hôpital de la Salpêtrière, 47 Boulevard de l'Hôpital, 75013, Paris, France.
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MeSH Terms
Apoptosis / drug effects*
Cell Differentiation / drug effects
Ceramides / biosynthesis
Cyclic AMP / pharmacology*
Free Radicals
Mitochondria / drug effects,  metabolism
NF-kappa B / metabolism
Nerve Growth Factors / pharmacology*
PC12 Cells
Reactive Oxygen Species / metabolism
Signal Transduction / drug effects*
Reg. No./Substance:
0/Ceramides; 0/Free Radicals; 0/NF-kappa B; 0/Nerve Growth Factors; 0/Reactive Oxygen Species; 60-92-4/Cyclic AMP

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