Identification of tocopherol-associated protein as an activin/TGF-beta-inducible gene in mast cells.
Previous studies have demonstrated that treatment with activin A and TGF-beta(1), members of the TGF-beta family, stimulated maturation of mouse bone marrow-derived cultured mast cells (BMMC), which was characterized by morphology and gene expression of mouse mast cell proteases (mmcps). In order to gain a better understanding of activin A- and TGF-beta(1)-induced maturation in mast cells, we investigated the genes that were up-regulated in response to treatment with these two members of the TGF-beta family. The cDNA microarray analyses indicated that in BMMC, five genes were induced by treatment with 4 nM activin A for 2 h. Tocopherol-associated protein (Tap) was one of the induced genes, and the Tap induction in response to activin A treatment was confirmed by real-time RT-PCR analyses. Treatment with TGF-beta(1) at 200 pM but not BMP-2 at 4 nM also increased Tap gene transcript in BMMC. Activin A-induced Tap expression was detected in BMMC but not in RAW264 macrophage-like cells, B16 melanoma cells or P19 embryonic carcinoma cells. Treatment with >1 muM SB431542, an inhibitor of activin and TGF-beta type I receptors ALK4/5, reduced responsiveness of Tap expression to TGF-beta(1), whereas <0.5 microM SB431542 effectively reduced TGF-beta(1)-induced expression of mmcp-1 and mmcp-7. These results suggest that inhibitory effects of SB431542 are different between TGF-beta-induced genes. Reporter assays indicated that Tap expression enhances transcription mediated by the activin/TGF-beta pathway. Thus, the present results suggest that Tap induction in response to activin/TGF-beta occurs predominantly in mast cells and serves as a positive regulator in activin/TGF-beta signaling.
Funaba
Masayuki
M
Laboratory of Nutrition, Azabu University School of Veterinary Medicine, 1-17-71 Fuchinobe, Sagamihara 229-8501, Japan. funaba@azabu-u.ac.jp
Murakami
Masaru
M
Ikeda
Teruo
T
Ogawa
Kenji
K
Tsuchida
Kunihiro
K
Sugino
Hiromu
H
D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors; D028341:Activins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D004149:Dioxoles / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D028322:Inhibin-beta Subunits / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008074:Lipoproteins / Q000235:genetics*; D020935:MAP Kinase Signaling System; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D051900:Smad3 Protein / Q000172:deficiency / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D002352:Carrier Proteins; D018076:DNA, Complementary; D004149:Dioxoles; D008074:Lipoproteins; D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C422405:activin A; C500212:tocopherol-associated protein, mouse; D028341:Activins; D028322:Inhibin-beta Subunits; D030201:Activin Receptors, Type I