Regulation of c-myc mRNA levels in normal human lymphocytes by modulators of cell proliferation.
Increased expression of the cellular oncogene c-myc has recently been demonstrated in some types of proliferating non-neoplastic cells, including lectin mitogen-stimulated lymphocytes, suggesting a role for this protooncogene in the regulation of growth of normal cells. Here we report the effects of several modulators of lymphocyte proliferation on the steady-state levels of c-myc mRNA in human peripheral blood mononuclear cells (PBMC). Stimulating PBMC with lectin mitogen phytohemagglutinin (PHA), phorbol ester phorbol 12-myristate 13-acetate, calcium ionophore ionomycin, or monoclonal antibody OKT3 (anti-antigen receptor complex) produced marked increases in c-myc mRNA levels within 3 hr. Recombinant interleukin 2 (rIL-2; Cetus) had little effect on c-myc expression but, in combination with PHA, it augmented levels of c-myc transcripts measured at 24 hr but not at 3 hr. Adding various inhibitors of lymphocyte proliferation to PHA-stimulated cultures revealed that cyclosporin A, dexamethasone, and OKT11A antibody (anti-sheep erythrocyte receptor) diminished levels of c-myc mRNA measured at 3 hr and 24 hr, whereas anti-Tac (anti-IL-2-receptor) inhibited at 24 hr but not at 3 hr. Thus, cyclosporin A, dexamethasone, and OKT11A interfere with early events of T-cell activation, whereas anti-Tac acts later. Hydroxyurea and 42/6 antibody (anti-transferrin receptor), which impair the G1----S transition in cycling cells, failed to inhibit c-myc expression and instead delayed the decrease in c-myc mRNA levels that normally occurs with the onset of DNA synthesis. These data indicate that c-myc is regulated (in normal lymphocytes) at several points in the cell cycle.
D000911:Antibodies, Monoclonal / Q000276:immunology; D002478:Cells, Cultured; D004987:Ethers / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007165:Immunosuppression Therapy; D007376:Interleukin-2 / Q000494:pharmacology; D007399:Interphase; D015759:Ionomycin; D008213:Lymphocyte Activation / Q000187:drug effects; D009857:Oncogenes; D010835:Phytohemagglutinins / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D004987:Ethers; D007376:Interleukin-2; D010835:Phytohemagglutinins; D012333:RNA, Messenger; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate