Activation of mitogen-activated protein kinase pathways during the death of PC12 cells is dependent on the state of differentiation.
PC12 cells that are differentiated with NGF and cAMP become totally dependent on these factors for their survival, unlike those that are differentiated with NGF alone. We have asked whether the MAP Kinases, ERKs, JNKs and p38s play a role in the cell death induced by withdrawal of trophic factors on NGF- and NGF/cAMP-differentiated PC12 cells. By Western-blot analyses with antibodies directed against the activated forms of these kinases, we show that when the trophic factors were withdrawn, ERK phosphorylation was reduced to very low levels within 1 h in both cases. Changes in the other enzymes were observed only in the NGF/cAMP-differentiated cells, in which the JNK phosphorylation increased about 160% by 6 h and that of p38 increased linearly to at least 18-fold throughout the cell death process. The increases in p38 and JNK phosphorylation were implicated in the death of the cells, since the p38 inhibitor PD169316 and the JNK inhibitor SP600125 were protective. These results demonstrate that the state of differentiation of PC12 cells, a model for the differentiation of sympathetic neurons, determines their vulnerability to cell death by modifying the state of phosphorylation and the regulation of specific kinases implicated in signal transduction pathways that are responsible for the survival or the death of these cells.
Lambeng
Nathalie
N
INSERM U.289, Hôpital de la Salpêtrière, 47 boulevard de l'Hôpital, 75013 Paris, France.
Willaime-Morawek
Sandrine
S
Mariani
Jean
J
Ruberg
Merle
M
Brugg
Bernard
B
D000818:Animals; D016923:Cell Death / Q000187:drug effects* / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000172:deficiency / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D020932:Nerve Growth Factor / Q000172:deficiency / Q000235:genetics; D009414:Nerve Growth Factors / Q000172:deficiency* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000196:embryology* / Q000201:enzymology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D009414:Nerve Growth Factors; D020932:Nerve Growth Factor; D000242:Cyclic AMP; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases