Membrane interaction and modulation of gene expression by tumor promoters

Phorbol ester tumor promoters bind to specific cellular receptors (probably protein kinase C) and modulate membrane structure and function and gene expression of target cells. Using cell culture systems, we are studying the interaction of phorbol esters with the cellular membrane and subsequent modulation of gene expression. Our recent results can be summarized as follows: 1) specific binding of phorbol esters to mammalian cells can be inhibited by a human placental factor, which we have partially purified and characterized. 2) Phorbol ester tumor promoters reversibly inhibit intercellular communication, as measured by electrical coupling and dye transfer between cultured cells, suggesting that they inhibit both ionic and molecular transfer between cells. 3) In vitro transformation of Balb/c 3T3 cells results in blockage of intercellular communication between normal and transformed cells, indicating that blocked intercellular communication may play a role in cell transformation. 4) 12-O-Tetradecanoylphorbol-13-acetate (TPA) can continuously inhibit differentiation and globin gene expression in Friend erythroleukemia cells, without affecting their growth rate, for about 3 years. Both globin gene expression and terminal differentiation of Friend cells occur again upon removal of TPA from culture medium during such long-term culture.