Overexpression of mitogen-activated protein kinase kinase kinase reversed cAMP inhibition of NF-kappaB in T cells.
cAMP inhibits T cell activation by acting as an antagonist for selective kinases and transcriptional factors. We have recently demonstrated that cAMP inhibited c-Jun N-terminal kinase (JNK) but left the mitogen-activated protein (MAP) kinase cascade almost unaffected in T lymphocytes. In accordance with recent reports, we also observed a selective suppression of nuclear factor NF-kappaB activation by cAMP. The possible link between the JNK cascade and NF-kappaB activation was demonstrated by the fact that the active form of MAP kinase kinase kinase (deltaMEKK), a constitutive activator of JNK, induced NF-kappaB but not AP-1, Oct, and NF-AT in T cells. In contrast, the induction of MAP kinase kinase (MEK)-MAP kinase did not stimulate NF-kappaB activity. The specific activation of NF-kappaB by a single MEKK-JNK cascade was thus unusual, given that the activation of other transcriptional elements in T cells requires at least two signal pathways. This was further confirmed by the fact that cAMP inhibition of NF-kappaB activation was reversed by overexpression of deltaMEKK.
Ho
H Y
HY
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
Lee
H H
HH
Lai
M Z
MZ
D000818:Animals; D000242:Cyclic AMP / Q000037:antagonists & inhibitors*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D005326:Fetal Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D051863:Host Cell Factor C1; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D050811:Octamer Transcription Factor-1; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D036122:Receptor, EphA4; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000037:antagonists & inhibitors
D004268:DNA-Binding Proteins; D005326:Fetal Proteins; C497693:Hcfc1 protein, mouse; D051863:Host Cell Factor C1; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D050811:Octamer Transcription Factor-1; C494166:Pou2f1 protein, mouse; D011518:Proto-Oncogene Proteins; C497594:Relb protein, mouse; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D051841:Transcription Factor RelB; D000242:Cyclic AMP; D011494:Protein Kinases; D020794:Receptor Protein-Tyrosine Kinases; D036122:Receptor, EphA4; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases