Abstract
Stimulation of cells with inducers of NF-kappaB such as LPS and IL-1 leads to the degradation of IkappaB-alpha and IkappaB-beta proteins and translocation of NF-kappaB to the nucleus. We now demonstrate that, besides the physical partitioning of inactive NF-kappaB to the cytosol, the transcriptional activity of NF-kappaB is regulated through phosphorylation of NF-kappaB p65 by protein kinase A (PKA). The catalytic subunit of PKA (PKAc) is maintained in an inactive state through association with IkappaB-alpha or IkappaB-beta in an NF-kappaB-IkappaB-PKAc complex. Signals that cause the degradation of IkappaB result in activation of PKAc in a cAMP-independent manner and the subsequent phosphorylation of p65. Therefore, this pathway represents a novel mechanism for the cAMP-independent activation of PKA and the regulation of NF-kappaB activity.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenosine Triphosphate / metabolism
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Amino Acid Sequence
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Animals
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Calpain / antagonists & inhibitors
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Cell Nucleus / metabolism
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Cyclic AMP / physiology*
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Cyclic AMP-Dependent Protein Kinases / chemistry
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Cyclic AMP-Dependent Protein Kinases / isolation & purification
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Cyclic AMP-Dependent Protein Kinases / metabolism*
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Cytosol / chemistry
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DNA-Binding Proteins / metabolism
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Enzymologic / physiology
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Lipopolysaccharides / pharmacology
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Lung / chemistry
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Molecular Sequence Data
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NF-kappa B / genetics*
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NF-kappa B / metabolism
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Phosphorylation
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Protein Binding / physiology
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Protein Structure, Tertiary
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Rabbits
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Transcriptional Activation / drug effects
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Transcriptional Activation / physiology*
Substances
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DNA-Binding Proteins
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Enzyme Inhibitors
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Lipopolysaccharides
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NF-kappa B
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Adenosine Triphosphate
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Cyclic AMP
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Cyclic AMP-Dependent Protein Kinases
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Calpain