TRANSCRIPTIONAL REGULATION OF THE BETA-CASEIN GENE BY CYTOKINES - CROSS-TALK BETWEEN STAT5 AND OTHER SIGNALING MOLECULES

The beta-casein promoter has been widely used to monitor the activatio n of STAT (signal transducer and activator of transcription)5 since ST AT5 was originally found as a mediator of PRL-inducible beta-casein ex pression. However, not only is expression of the beta-casein gene regu lated by STAT5 but it is also affected by other molecules such as gluc ocorticoid and Ras. In this report, we describe the transcriptional re gulation of the beta-casein gene by cytokines in T cells. We have foun d that the beta-casein gene is expressed in a cytotoxic T cell line, C TLL-2, in response to interleukin-2 (IL-2), which activates STAT5. Whi le IL-4 does not activate STAT5, it induces expression of STAT5-regula ted genes in CTLL-2, i.e. beta-casein, a cytokine-inducible SH2-contai ning protein (CIS), and oncostatin M (OSM), suggesting that STAT6 acti vated by IL-4 substitutes for the function of STAT5 in T cells. IL-2-i nduced beta-casein expression was enhanced by dexamethasone, and this synergistic effect of Dexamethasone requires the sequence between -155 and -193 in the beta-casein promoter. Coincidentally, a deletion of t his region enhanced the Il-e-induced expression of beta-casein. Expres sion of an active form of Ras, Ras(G12V), suppressed the IL-2-induced beta-casein and OSM gene expression, and the negative effect of Ras is mediated by the region between -105 and -193 in the p-casein promoter . In apparent contradiction, expression of a dominant negative form of Ras, RasN17, also inhibited IL-2-induced activation of the promoter c ontaining the minimal beta-casein STAT5 element as well as the promote rs of CIS and OSM. In addition, Ras(G12V) complemented signaling by an erythropoietin receptor mutant defective in Ras activation and augmen ted the activation of the beta-casein promoter by the mutant erythropo ietin receptor signaling, suggesting a possible role of Ras in Stat5-m ediated gene expression. These results collectively reveal a complex i nteraction of STATE with other signaling pathways and illustrate that regulation of gene expression requires integration of opposing signals .