TGF-β1 is a multifunctional cytokine that mediates diverse biological processes. However, the mechanisms by which the intracellular signals of TGF-β1 are terminated are not well understood. Here, we demonstrate that DRAK2 serves as a TGF-β1-inducible antagonist of TGF-β signaling. TGF-β1 stimulation rapidly induces DRAK2 expression and enhances endogenous interaction of the type I TGF-β receptor with DRAK2, thereby blocking R-Smads recruitment. Depletion of DRAK2 expression markedly augmented the intensity and the extent of TGF-β1 responses. Furthermore, a high level of DRAK2 expression was observed in basal-like and HER2-enriched breast tumors and cell lines, and depletion of DRAK2 expression suppressed the tumorigenic ability of breast cancer cells. Thus, these studies define a function for DRAK2 as an intrinsic intracellular antagonist participating in the negative feedback loop to control TGF-β1 responses, and aberrant expression of DRAK2 increases tumorigenic potential, in part, through the inhibition of TGF-β1 tumor suppressor activity.

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SummaryThis study demonstrates the effect of soybean components on the tumor necrosis factor-␣ (TNF-␣ )-induced production of interleukin-8 (IL-8), one of the major inflammatory chemokines, in intestinal epithelial-like Caco-2 cells. Among the soybean components, an isoflavone fraction (IFF) suppressed the TNF-␣ -induced IL-8 secretion by Caco-2 cells in a dose-dependent manner, whereas a soyasaponin fraction and soypeptide fraction had no significant effect on TNF-␣ -induced IL-8 secretion. The IL-8 secretion induced by hydrogen peroxide and by IL-1 ␤ was not suppressed by IFF, suggesting that the inhibitory effect of isoflavone was specific for the TNF-␣ -induced regulation of IL-8. The increased expression of IL-8 mRNA by TNF-␣ was almost completely suppressed by IFF. Furthermore, the transcriptional activity of the human IL-8 promoter was increased by the TNF-␣ treatment, and IFF significantly suppressed the IL-8 promoter activity. These results indicate that IFF suppressed TNF-␣ -induced IL-8 production at the transcriptional level in human intestinal Caco-2 cells, suggesting IFF of soybean as a promising food component for preventing intestinal inflammation such as inflammatory bowel disease.

Summary Amino acids in enterocytes are thought to be absorbed in the intestinal epithelium via various types of amino acid transport, although the regulation of these amino acid transport systems has not been elucidated. We examined in the present study the effect of several inhibitors involved in mRNA and protein synthesis, and of protein translocation on the L -leucine (Leu) uptake in human intestinal epithelial-like Caco-2 cells. Culturing Caco-2 cells with cycloheximide (CHX) enabled the L -Leu uptake to be significantly increased in a dose-and time-dependent manner. The uptake of L -lysine (Lys) was also increased by the CHX treatment, whereas the uptake of L -glutamate, taurine, and Gly-Gln was not changed. Among the two transport systems, b 0, ϩ and y