Interferon-alpha selectively activates the beta isoform of protein kinase C through phosphatidylcholine hydrolysis.
The early events that occur after interferon binds to discrete cell surface receptors remain largely unknown. Human leukocyte interferon (interferon-alpha) rapidly increases the binding of [3H]phorbol dibutyrate to intact HeLa cells (ED50 = 100 units/ml), a measure of protein kinase C activation, and induces the selective translocation of the beta isoform of protein kinase C from the cytosol to the particulate fraction of HeLa cells. The subcellular distribution of the alpha and epsilon isoforms is unaffected by interferon-alpha treatment. Activation of protein kinase C by phorbol esters mimics the inhibitory action of interferon-alpha on HeLa cell proliferation and down-regulation of protein kinase C blocks the induction of antiviral activity by interferon-alpha in HeLa cells. Increased phosphatidylcholine hydrolysis and phosphorylcholine production is accompanied by diacylglycerol production in response to interferon. However, inositol phospholipid turnover and free intracellular calcium concentration are unaffected. These results suggest that the transient increase in diacylglycerol, resulting from phosphatidylcholine hydrolysis, may selectively activate the beta isoform of protein kinase C. Moreover, the activation of protein kinase C is a necessary element in interferon action on cells.
Pfeffer
L M
LM
Rockefeller University, New York, NY 10021.
Strulovici
B
B
Saltiel
A R
AR
D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D003600:Cytosol / Q000201:enzymology; D004075:Diglycerides / Q000378:metabolism; D004789:Enzyme Activation; D006367:HeLa Cells / Q000201:enzymology; D006801:Humans; D006868:Hydrolysis; D007370:Interferon Type I / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D015240:Phorbol 12,13-Dibutyrate / Q000378:metabolism; D010713:Phosphatidylcholines / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D011955:Receptors, Drug / Q000378:metabolism; D011994:Recombinant Proteins; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects / Q000254:growth & development
D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D004075:Diglycerides; D007370:Interferon Type I; D007527:Isoenzymes; D010713:Phosphatidylcholines; D011955:Receptors, Drug; D011994:Recombinant Proteins; C083141:phorbol ester binding protein; C027776:phorbol ester receptor; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate