sq-23377 and Sezary-Syndrome

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.

Topics: Calcium; Cell Nucleus; Cytoplasm; Enzyme Activation; Enzyme Induction; Humans; Ionomycin; Isoenzymes; Leukemia-Lymphoma, Adult T-Cell; Lymphocyte Activation; Muromonab-CD3; Protein Kinase C; Protein Serine-Threonine Kinases; Proto-Oncogene Mas; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-pim-1; Proto-Oncogene Proteins c-raf; Proto-Oncogenes; Receptor-CD3 Complex, Antigen, T-Cell; Receptors, Antigen, T-Cell; RNA, Messenger; Sezary Syndrome; Signal Transduction; Skin Neoplasms; T-Lymphocytes; Tetradecanoylphorbol Acetate; Transcription, Genetic; Transfection; Tumor Cells, Cultured