Regulation of gene expression by tumor promoters. III. Complementation of the developmental program in myeloid leukemic cells by regulating mRNA production and mRNA translation.

Regulation of gene expression has been analysed in different clones of mouse myeloid leukemic cells treated with the tumor promoter 12-0-tetradecanoyl-phorbol-13-acetate (TPA), the macrophage- and granulocyte-inducing protein MGI, and combined treatment with TPA and MGI. Two-dimensional gel electrophoresis was used to measure changes in the rate of synthesis of specific proteins and in the amount of corresponding translatable mRNAs assayed in the reticulocyte cell-free translation system. TPA induced different subsets of differentiation-associated protein changes in the different clones and the degree of response to TPA was not necessarily related to the degree of response to MGI. It is shown that TPA can induce protein changes either by inducing the synthesis of new mRNA, by increasing or decreasing the amount of pre-existing mRNA, or by modulating the translation of a constant amount of mRNA. Combined treatment with TPA and MGI resulted in an enhancement of protein changes induced by MGI or TPA alone and induced differentiation-associated protein changes not induced by either compound separately in differentiation-defective clones. This complementation of gene expression appeared to be due to each compound inducing functions not induced by the other, so that the combined treatment resulted in new gene expression. Complementation also occurred at the level both of mRNA production and of mRNA translation. It is suggested that the ability of TPA to regulate gene expression at the level of mRNA production and mRNA translation and to complement changes in gene expression induced by other compounds such as MGI are important functions for its role as a tumor promoter.