The possible involvement of protein kinase C in transducing the growth suppressive signals of interferons was studies in this work in two different hematopoietic cell lines. Chronic exposure of human Burkitt lymphoma and mouse M1 myeloblastic cell lines to phorbol myristate acetate (PMA), reduced by more than 90% the PKC protein levels and enzymatic activity in cell extracts. The depletion of PKC from cells abrogated the ability of IFN (alpha + beta) to arrest cell growth at the G0/G1 resting phase of the cell cycle. In contrast, other responses to IFN such as the induction of (2'-5') oligoadenylate synthetase gene, continued to take place at the same dose response pattern thus excluding the possibility that early targets in the pathway, such as the number or affinity of IFN cell surface receptors might be affected by PMA. The same prolonged treatment of M1 cells with PMA did not interfere with the ability of another cytokine, transforming growth factor beta (TGF-beta), to induce the normal type of G0/G1 arrest further supporting the specificity of the effect towards IFN responses. Unexpectedly, depletion of PKC from cells did not interfere with the negative effects of IFN on c-myc mRNA and protein expression in spite of the direct involvement of this molecular event in growth responses to IFN. The putative PKC dependent molecular event could therefore function either downstream to or in combination with the reduction in c-myc protein levels, providing a necessary but not a sufficient step to arrest cell cycle progression at the G0/G1 phase.