Abstract
Chemotherapeutic agents such as cisplatin induce persistent activation of N-terminal c-Jun Kinase, which in turn mediates induction of apoptosis. By using a common MAPK Kinase, MEKK1, cisplatin also activates the survival transcription factor NFkappaB. We have found a cross-talk between c-Jun expression and NFkappaB transcriptional activation in response to cisplatin. Fibroblast derived from c-jun knock out mice are more resistant to cisplatin-induced cell death, and this survival advantage is mediated by upregulation of NFkappaB-dependent transcription and expression of MIAP3. This process can be reverted by ectopic expression of c-Jun in c-jun(-/-) fibroblasts, which decreases p65 transcriptional activity back to normal levels. Negative regulation of NFkappaB-dependent transcription by c-jun contributes to cisplatin-induced cell death, which suggests that inhibition of NFkappaB may potentiate the antineoplastic effect of conventional chemotherapeutic agents.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Apoptosis / physiology
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Cell Line
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Cell Survival*
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Cisplatin / pharmacology
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Down-Regulation / physiology
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Enzyme Activation
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Fas Ligand Protein
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Gene Expression Regulation
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Genes, Reporter
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HIV / genetics
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism
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Humans
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Inhibitor of Apoptosis Proteins
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 1*
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism*
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NF-kappa B / metabolism*
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Protein Serine-Threonine Kinases / metabolism*
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Proteins / genetics
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Proteins / metabolism
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Signal Transduction / physiology
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Transcription Factor RelA
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Transcription Factors / metabolism
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Transcription, Genetic
Substances
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Antineoplastic Agents
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Birc4 protein, mouse
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FASLG protein, human
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Fas Ligand Protein
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Fasl protein, mouse
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Inhibitor of Apoptosis Proteins
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Membrane Glycoproteins
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NF-kappa B
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Proteins
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Transcription Factor RelA
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Transcription Factors
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Protein Serine-Threonine Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 1
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MAP3K1 protein, human
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Map3k1 protein, mouse
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Histone Deacetylases
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Cisplatin