12-Tetradecanoylphorbol-13-acetate (TPA)-induced differentiation of U937 promonocytes leads to a 30-fold increase in transforming growth factor ,Bl (TGF-,1l) gene expression, and this effect results from a stabilized mRNA. Similar up-regulation was detected in TPA-treated K562 erythroblasts but was absent from cell lines that do not differentiate in response to TPA. Related studies in vitro showed that postnuclear extracts of U937 promonocytes contain a ribonuclease system that degrades TGF-11 mRNA selectively and that this system is completely blocked by prior treatment of the cells with TPA. These data identify a new mechanism for regulating TGF-pl mRNA levels and allow us to establish the overall basis for control of TGF-,B1 gene expression by activation of protein kinase C. Our results also provide a new basis for understanding the long-term up-regulation of TGF-,Bl gene expression that can accompany hematopoietic cell differentiation.Transforming growth factor 13 (TGF-,11) has widespread and complex effects on cells, including both stimulation and inhibition of growth and differentiation (37,42,61,63). The specific effect of TGF-1l depends on many variables, including cell type and the presence of other growth factors (7,16,49,58). Potent effects are particularly evident in blood cells; TGF-131 regulates monocyte chemotaxis and inhibits T-cell, B-cell, and NK cell function (26,27,50,65). Several differentiated hematopoietic cell types (6,19,26,27) express relatively high levels of TGF-,1l mRNA, suggesting the potential for autocrine and paracrine effects of the growth factor on blood cell physiology and pathology.The pervasive effects of TGF-131 emphasize the need to understand mechanisms that regulate expression of this protein. Several studies have shown that biosynthesis of TGF-p1 can be regulated by controls on transcription (28-30, 33, 56). Two active promoters have been characterized in the human by transfection studies with chimeric chloramphenicol acetyltransferase constructs and by structural analysis of TGF-131 mRNAs. Enhancer domains for several established transcription factors have also been identified in these promoter regions. Phorbol esterresponsive elements (TREs) have been identified in both the upstream and downstream domains of the TGF-13 gene. The existence of these TREs explains, at least in part, the observation that activators of protein kinase C such as 12-tetradecanoylphorbol-13-acetate (TPA) and platelet-derived growth factor stimulate expression of TGF-,11 mRNA in target cells (1,56,64). TGF-131 stimulates transcription of its own gene, and the cis-acting sequences mediating this effect appear to coincide with upstream TREs (28).The importance of transcriptional regulation notwithstanding, many studies have described clear examples in which posttranscriptional controls play major roles in determining overall gene expression (13,14). For example, his-* Corresponding author.tone mRNAs are selectively stabilized in S phase of the cell cycle (18, 60), transcripts encoding colony-sti...