Cell stress and MEKK1-mediated c-Jun activation modulate NFkappaB activity and cell viability.
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.
Instituto de Investigaciones Biomédicas Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, Spain.
Isabel
I
Sánchez-Pérez
Salvador Aznar
SA
Benitah
Montserrat
M
Martínez-Gomariz
Juan Carlos
JC
Lacal
Rosario
R
Perona
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D015536:Down-Regulation / Q000502:physiology; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006678:HIV / Q000235:genetics; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D000970:Antineoplastic Agents; C107521:Birc4 protein, mouse; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011506:Proteins; D051996:Transcription Factor RelA; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; C482578:Map3k1 protein, mouse; D006655:Histone Deacetylases; D002945:Cisplatin