Transforming growth factor 0 (TGFP) is a multifunctional polypeptide that regulates proliferation, differentiation, and other functions of many cell types. The pathway of TGFI8 signal transduction in cells is unknown. We report here that an early effect of TGFOI is an enhancement of the expression of two genes encoding serum-and phorbol ester tumor promoter-regulated transcription factors: the junB gene and the c-jun proto-oncogene, respectively. This stimulation was observed in human lung adenoc'arcinoma A549 cells which were growth inhibited by TGFj, AKR-2B mouse embryo fibroblasts which were growth stimulated by TGFI, and K562 human erythroleukemia cells, which were not appreciably affected in their growth by TGFI.

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Treatment of quiescent cultures of mouse embryo-derived AKR-2B cells with transforming growth factor beta resulted in an induction of basic fibroblast growth factor (bFGF) mRNA and bFGF protein in the stimulated cells. In contrast to bFGF, acidic fibroblast growth factor (aFGF) was not induced by TGF beta. The mitogenic effect of transforming growth factor beta on AKR-2B cells may be mediated by the induction of bFCF in these cells.

Molecular cloning has revealed that erythroid potentiating activity (EPA) and tissue inhibitor of metalloproteinases (TIMP) represent two distinct activities of a single protein. We have studied the expression of the EPA/TIMP gene at the mRNA and protein levels during 12-O- tetradecanoyl-phorbol-13-acetate (TPA)-induced megakaryoblastic differentiation of K562 human chronic myeloid leukemia cells. Northern hybridization analysis showed that the EPA/TIMP mRNA was increased within 3 hours of TPA-induction and reached maximal levels (about 50- fold induction) during the first day of treatment. The expression of mRNAs for two major metalloproteinases, collagenase-I and stromelysin, were activated in parallel in the differentiation-induced K562 cells. The increase of EPA/TIMP mRNA correlated with increased EPA/TIMP protein biosynthesis and secretion: the TPA-induced cells secreted substantially enhanced amounts of metabolically labeled proteins, of which EPA/TIMP represented up to 50% after the first day of treatment (over 100-fold induction). The induction of EPA/TIMP mRNA was associated with its increased transcription. EPA/TIMP induction required continuous protein synthesis, being completely inhibited by addition of the protein synthesis inhibitor cycloheximide simultaneously with TPA, but only partially inhibited in a time- dependent manner if cycloheximide was added after TPA. Unlike in other cells tested, the jun and c-fos transcription factor mRNAs showed a prolonged biphasic induction response in K562 cells during TPA treatment. This response was associated with enhanced activity of a transfected recombinant reporter plasmid containing binding sites for the jun/fos transcription factor complex (AP-1) similar to the TPA- responsive element (TRE) sequence we found in the EPA/TIMP gene promoter. We suggest that the induction of EPA/TIMP and several other genes specific for the differentiating K562 cells may be a consequence of the sustained activation of immediate early genes encoding transcription factors, such as jun and c-fos.