pim-1 proto-oncogene expression in anti-CD3-mediated T cell activation is associated with protein kinase C activation and is independent of Raf-1.
We have studied pim-1 proto-oncogene expression in human T cell responses to Ag receptor-generated signals. The pim-1 gene encodes a serine/threonine protein kinase that is expressed primarily in cells of hematopoietic lineage and is implicated in the intracellular signaling processes accompanying lymphocyte activation. We show here that pim-1 mRNA expression is rapidly induced after receptor cross-linking with anti-CD3 Abs. We examined the linkage of pim-1 expression to known signaling pathways generated through the T cell Ag receptor. pim-1 mRNA was not substantially induced after elevation of intracellular free Ca2+. In contrast, PMA, which directly activates PKC, induced rapid pim-1 expression. Further, anti-CD3- or PMA-induced pim-1 expression was markedly reduced by various PKC inhibitors and by deficiency of the PKC epsilon isoform in a mutant T cell line. Thus, T cell Ag receptor-linked pim-1 expression appears to be coupled to the PKC component of transmembrane signaling. Because the activation of protein kinase C has been shown to activate Raf-1 kinase activity, the involvement of Raf-1 in pim-1 expression was also investigated using a human T cell line stably transfected with an inducible Raf expression vector. Although the overexpression of activated Raf was shown to cause a substantial increase in IL-2 expression, no discernible effects on pim-1 were apparent. In addition, we examined transcriptional and post-transcriptional mechanisms involved in PKC-mediated pim-1 expression and observed that both transcriptional and post-transcriptional mechanisms are coordinately involved in the up-regulation of the pim-1 proto-oncogene.
Department of Veterans Affairs, Boise, ID 83702, USA.
D
D
Wingett
A
A
Long
D
D
Kelleher
N S
NS
Magnuson
D002118:Calcium / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000502:physiology; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology; D008213:Lymphocyte Activation / Q000502:physiology*; D016853:Muromonab-CD3 / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D051573:Proto-Oncogene Proteins c-pim-1; D019908:Proto-Oncogene Proteins c-raf; D011519:Proto-Oncogenes; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D012751:Sezary Syndrome / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D012878:Skin Neoplasms / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
D007527:Isoenzymes; C000715470:MAS1 protein, human; D016853:Muromonab-CD3; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011948:Receptors, Antigen, T-Cell; D015759:Ionomycin; C496634:PIM1 protein, human; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1; D019908:Proto-Oncogene Proteins c-raf; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium