Modulation of surface transferrin receptor activity has been associated with leukemia cell differentiation and proliferation. To examine the mechanisms involved in regulating this event, receptor protein and mRNA levels were measured in HL-60 promyelocytic leukemia cells induced to differentiate along the myelocytic and monocytic pathways. Transferrin receptor down-regulation which occurs during granulocytic differentiation by dimethyl sulfoxide, retinoic acid, or aclacinomycin A appears to be kinetically compatible with reduced biosynthesis resulting from reductions in the level of steady-state mRNA. In contrast, genetic modulation does not appear to mediate the initial receptor down-regulation seen during 12-O-tetradecanoylphorbol-13-acetate-induced monocytic differentiation. However, a reduction in levels of receptor message appears to contribute to the maintenance of diminished transferrin receptor activity in these 12-O-tetradecanoylphorbol-13-acetate-treated cells. A common feature of myelocytic and monocytic differentiating cells is the complete inhibition of cellular proliferation observed within 10 to 16 h following a four-fold reduction in surface transferrin receptor. We conclude that the early decline in transferrin receptor levels precludes its regulation as a consequence of the decrease in proliferation, but rather implicates its role in the programmed cessation of growth which is requisite for the terminal differentiation of these cells.
Supported in part by USPHS Grant CA-02817 from the National Cancer Institute.