Abstract
MAPK-dependent activation of AP-1 protein c-Jun is involved in PC12 cell differentiation and apoptosis. However, the role of other AP-1 proteins and their connection to MAPKs during growth, differentiation and apoptosis has remained elusive. Here we studied the activation of AP-1 proteins in response to ERK, JNK, and p38 signaling upon NGF, EGF and anisomycin exposures. All treatments caused different kinetics and strength of MAPK and AP-1 activities. NGF induced persistent ERK and AP-1 activities, whereas upon EGF and anisomycin exposures, their activities were only weakly and transiently induced. The sustained AP-1 activity was associated with concomitant c-Fos and c-Jun expression and phoshorylation, which were JNK and ERK dependent. While inhibition of the ERK, JNK, and p38 activities partially prevented AP-1 activity and suppressed differentiation, none of them was required for anisomycin-induced apoptosis. The importance of c-Fos and c-Jun as mediators of differentiation was demonstrated by the findings that the corresponding siRNAs suppressed NGF-induced neurite outgrowth. However, the capacity of c-Fos to promote differentiation required cooperation with Jun proteins. In contrast, Fra-2 expression was not required for the differentiation response. Together, the results show that sustained c-Jun and c-Fos activities mediate MAPK signaling and are essential for differentiation of PC12 cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology
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Cell Differentiation / drug effects
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Cell Differentiation / physiology*
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Cell Enlargement / drug effects
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Down-Regulation / physiology
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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Extracellular Signal-Regulated MAP Kinases / drug effects
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Fos-Related Antigen-2 / metabolism
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Intercellular Signaling Peptides and Proteins / metabolism
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Intercellular Signaling Peptides and Proteins / pharmacology
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JNK Mitogen-Activated Protein Kinases / drug effects
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JNK Mitogen-Activated Protein Kinases / metabolism
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology*
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism*
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PC12 Cells
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Protein Synthesis Inhibitors / pharmacology
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Proto-Oncogene Proteins c-fos / genetics
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Proto-Oncogene Proteins c-fos / metabolism*
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Proto-Oncogene Proteins c-jun / genetics
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Proto-Oncogene Proteins c-jun / metabolism*
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RNA Interference / physiology
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Rats
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Stress, Physiological / metabolism*
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Stress, Physiological / physiopathology
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Transcription Factor AP-1 / drug effects
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Transcription Factor AP-1 / genetics
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Transcription Factor AP-1 / metabolism
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p38 Mitogen-Activated Protein Kinases / drug effects
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Fos-Related Antigen-2
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Fosl2 protein, rat
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Intercellular Signaling Peptides and Proteins
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Protein Synthesis Inhibitors
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Proto-Oncogene Proteins c-fos
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Proto-Oncogene Proteins c-jun
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Transcription Factor AP-1
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Extracellular Signal-Regulated MAP Kinases
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JNK Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases