Abstract
Engagement of the type II IFN (IFN-gamma) receptor results in activation of the Janus kinase-Stat pathway and induction of gene transcription via IFN-gamma-activated site (GAS) elements in the promoters of IFN-gamma-inducible genes. An important event in IFN-gamma-dependent gene transcription is phosphorylation of Stat1 on Ser(727), which is regulated by a kinase activated downstream of the phosphatidylinositol 3'-kinase. Here we provide evidence that a member of the protein kinase C (PKC) family of proteins is activated downstream of the phosphatidylinositol 3'-kinase and is engaged in IFN-gamma signaling. Our data demonstrate that PKCdelta is rapidly phosphorylated during engagement of the type II IFNR and its kinase domain is induced. Subsequently, the activated PKCdelta associates with a member of the Stat family of proteins, Stat1, which acts as a substrate for its kinase activity and undergoes phosphorylation on Ser(727). Inhibition of PKCdelta activity diminishes phosphorylation of Stat1 on Ser(727) and IFN-gamma-dependent transcriptional regulation via IFN-gamma-activated site elements, without affecting the phosphorylation of the protein on Tyr(701). Thus, PKCdelta is activated during engagement of the IFN-gamma receptor and plays an important role in IFN-gamma signaling by mediating serine phosphorylation of Stat1 and facilitating transcription of IFN-gamma-stimulated genes.
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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Acetophenones / pharmacology
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Benzopyrans / pharmacology
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Carbazoles / pharmacology
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology
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Enzyme Activation / drug effects
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Enzyme Activation / immunology
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Enzyme Inhibitors / pharmacology
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Humans
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Imidazoles / pharmacology
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Indoles / pharmacology
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Interferon gamma Receptor
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Interferon-gamma / metabolism
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Interferon-gamma / physiology*
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism
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Isoenzymes / physiology
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Mesylates / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphatidylinositol 3-Kinases / physiology
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Phosphorylation / drug effects
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Phosphoserine / metabolism
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / metabolism*
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Protein Kinase C / physiology
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Protein Kinase C-delta
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Pyridines / pharmacology
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Pyrroles / pharmacology
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Receptors, Interferon / metabolism
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STAT1 Transcription Factor
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Signal Transduction / immunology
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Trans-Activators / metabolism
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Trans-Activators / physiology
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Tumor Cells, Cultured
Substances
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5,21 - 12,17-dimetheneo-18H-dibenzo(i,o)pyrrolo(3,4-1)(1,8)diazacyclohexandecine-18,10(19H)dione,8((dimethylamino)methyl)-6,7,8,9,10,11-hexahydro,monomethanesulfonate
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Acetophenones
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Benzopyrans
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Carbazoles
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DNA-Binding Proteins
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Enzyme Inhibitors
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Imidazoles
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Indoles
-
Isoenzymes
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Mesylates
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Pyridines
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Pyrroles
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Receptors, Interferon
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STAT1 Transcription Factor
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STAT1 protein, human
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Trans-Activators
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Go 6976
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Phosphoserine
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Interferon-gamma
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rottlerin
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Phosphatidylinositol 3-Kinases
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PRKCD protein, human
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Protein Kinase C
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Protein Kinase C-delta
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SB 203580