Human T-cell lymphotropic virus type 1 Tax1 activation of NF-kappa B: involvement of the protein kinase C pathway.
Human T-cell lymphotropic virus type 1 Tax1 induces the activation and nuclear localization of the cellular transcription factor, NF-kappa B. Treatment of cells with calphostin C, a protein kinase C (PKC) inhibitor, blocked induction of NF-kappa B DNA binding activity in human T-cell lymphotropic virus type 1-transformed C81 cells and Tax1-stimulated murine pre-B cells, suggesting that PKC was an important intermediate in the NF-kappa B induction pathway. We further demonstrate that Tax1 associates with, and activates, PKC. PKC was coimmunoprecipitated with anti- Tax1 sera from Tax1-expressing MT4 extracts and Jurkat extracts in the presence of exogenous Tax1 protein. In addition, the glutathione-S-transferase-Tax1 protein bound specifically to the alpha, delta, and eta PKC isoenzymes synthesized in rabbit reticulocyte lysates. The addition of Tax1 to in vitro kinase reaction mixtures leads to the phosphorylation of Tax1 and an 18-fold increase in the autophosphorylation of PKC. Transfection of Jurkat cells with wild-type Tax1 stimulated membrane translocation of PKC. In contrast, Tax1 mutant M22, which fails to stimulate NF-kappa B-dependent transcription, failed to stimulate membrane translocation of PKC. Tax1 did not directly increase PKC phosphorylation of I kappa B alpha. Our results are consistent with a model in which Tax1 interacts with PKC and stimulates membrane translocation and triggering of the PKC pathway. Subsequent steps in the PKC cascade likely stimulate phosphorylation of I kappa B alpha.
Lindholm
P F
PF
Laboratory of Molecular Virology, National Cancer Institute, Bethesda, Maryland 20892-5005, USA.
Tamami
M
M
Makowski
J
J
Brady
J N
JN
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D004279:DNA, Viral; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016356:Gene Products, tax / Q000235:genetics / Q000502:physiology*; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000096:biosynthesis*; D009281:Naphthalenes / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D014176:Protein Biosynthesis; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051841:Transcription Factor RelB; D014157:Transcription Factors; D014162:Transfection
D004279:DNA, Viral; D004791:Enzyme Inhibitors; D016356:Gene Products, tax; D016328:NF-kappa B; D009281:Naphthalenes; D011518:Proto-Oncogene Proteins; C497593:RELB protein, human; C497594:Relb protein, mouse; D014157:Transcription Factors; D051841:Transcription Factor RelB; D011493:Protein Kinase C; C058819:calphostin C