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Biological Mechanisms of Phorbol Myristate Acetate-induced Inhibition of Proadipocyte Differentiation¹

Section of Experimental Pathology, Departments of Pathology and Cell Biology, Mayo Clinic and Foundation, Rochester, Minnesota 55905

The differentiation of murine proadipocytes can be induced by two different methods: 1.) by culture of high-density proadipocytes in medium containing high concentrations of serum to which is added a variety of hormones and 2.) by culture of low-density proadipocytes in heparinized medium containing only human plasma. Phorbol myristate acetate influences differentiation in both culture systems, but the biological mechanisms by which phorbol myristate exerts its effect have not been established previously. In this regard, we have recently shown that five distinct steps mediate the integrated control of proadipocyte proliferation and differentiation (J. Cell Biol., 94: 400, 1982). Three steps are involved in the differentiation process: (a) growth arrest at a distinct state in the G₁ phase of the cell cycle (G_D); (b) nonterminal differentiation; and (c) terminal differentiation. Two steps antagonize the differentiation process and cause proliferation. These are (a) induction of loss of the differentiated phenotype and (b) reinitiation of proliferation. In this paper, we have therefore examined the effects of the tumor promoter phorbol myristate acetate on each step of integrated control of proliferation and differentiation in high- and low-density proadipocytes. The results show that in the high-density system, phorbol myristate acetate can have the following effects under appropriate experimental conditions. It can: (a) block growth arrest at G_D; (b) inhibit nonterminal differentiation; (c) promote loss of the differentiated phenotype; and (d) promote the proliferation of G_D-arrested cells. In the low-density system by contrast, phorbol myristate acetate (a) does not block G_D arrest and (b) does not block nonterminal differentiation but (c) does promote loss of the differentiated phenotype and (d) does promote the proliferation of G_D-arrested cells. These results show that the mechanisms by which phorbol myristate acetate affects differentiation are significantly influenced by a variety of factors which include changes in the culture medium, cell density, and cell-cell contact. Therefore, attempts to correlate general effects of phorbol myristate acetate on the control of cell proliferation and differentiation with its action as a tumor promoter may not be justified. We suggest that only actions of phorbol myristate acetate which selectively affect initiated cells should be considered to be relevant to the mechanisms of promotion of carcinogenesis.

¹ This research was supported in part by NIH Grant CA 28240 and by the Mayo Foundation to R. E. S.

² To whom requests for reprints should be addressed.

Received 5/12/82. Accepted 10/ 8/82.

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