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Regulation of growth and differentiation by phorbol esters and the mechanism of tumor promotion.

Our studies on the growth and differentiation of normal and malignant myeloid cells have shown that tumor-promoting, but not nonpromoting, phorbol esters can induce the production of an specifically increase cell susceptibility to the normal myeloid inducers of growth and differentiation, the macrophage- and granulocyte-inducing proteins MGI. In some clones of myeloid leukemic cells, the tumor promoters induced cell differentiation via the production of MGI. In other clones that were not inducible by adding only the tumor promoters or MGI, the tumor promoters induced differentiation by increasing cell susceptibility to externally added MGI. Normal myeloid progenitor cells, unlike leukemic cells, require MGI for cell viability and multiplication. Our studies with these normal cells have shown, that tumor promoters can also induce cell multiplication both by the induction of MGI and by increasing cell susceptibility to externally added MGI. We suggest that by the above mechanisms of inducing the production and increasing cell susceptibility to normal regulators of cell multiplication and differentiation, tumor-promoting phorbol esters can exert pleiotropic effects, the nature of these effects depending on which molecules are being regulated in the treated cells.