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Specific High-Affinity Binding of the Phorbol Ester Tumor Promoter 12-O-Tetradecanoylphorbol-13-acetate to Isolated Nuclei and Nuclear Macromolecules in Mouse Epidermis¹

McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53706

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) binds reversibly and with high affinity and specificity to nuclear macromolecules in mouse epidermis. The dissociation constants determined from Scatchard analysis of epidermal nuclei and nuclear macromolecules are 3.58 ± 0.66 (S.E.) and 2.18 ± 0.54 nM, respectively. The solubilization of TPA receptors from epidermal nuclei by DNase I was examined. Following a 20-min digestion at 22°, more than a 2-fold increase in specific TPA binding was observed in the supernatant relative to non-nuclease-treated nuclei (0.71 versus 0.32 pmol/mg protein, respectively). Our data indicate that epidermal nuclei contain saturable and specific TPA-binding macromolecules and that these binding components may be associated with regions of chromatin that are preferentially susceptible to nucleolytic cleavage. These data suggest the existence of nuclear receptors for the phorbol ester tumor promoters. These observations may necessitate a more critical assessment of plasma membrane binding as the sole binding site responsible for triggering the multistep process of tumor promotion in mouse epidermis.

¹ This work was supported by NIH Grants CA-22484, CA-07175, and CA-06591-02 and by American Cancer Society Institutional Research Grant IN-35.

² To whom requests for reprints should be addressed.

Received 10/29/81. Accepted 5/28/82.