Regulation of c-myc mRNA levels in normal human lymphocytes by modulators of cell proliferation.

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Abstract
Increased expression of the cellular oncogene c-myc was recently demonstrated in some types of proliferating non-neoplastic cells, including lectin mitogen-stimulated lymphocytes, suggesting a role for this proto-oncogene in the regulation of growth of normal cells. The effects of several modulators of lymphocyte proliferation on the steady-state levels of c-myc mRNA in human peripheral blood mononuclear cells (PBMC) are reported. Stimulating PBMC with lectin mitogen phytohemagglutinin (PHA), phorbol ester phorbol 12-myristate 13-acetate, Ca ionophore ionomycin, or monoclonal antibody OKT3 (anti-antigen receptor complex) produced marked increases in c-myc mRNA levels within 3 h. 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 h but not at 3 h. 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 h and 24 h, whereas anti-Tac (anti-IL-2 receptor) inhibited at 24 h but not at 3 h. 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 .fwdarw. 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. Apparently, c-myc is regulated (in normal lymphocytes) at several points in the cell cycle.