Hepatocyte Growth Factor Induces Transglutaminase Activity That Negatively Regulates the Growth Signal in Primary Cultured Hepatocytes |
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Authors: | Shinsuke Katoh Noriko Nakagawa Yoshiko Yano Kumiko Satoh Hiroyuki Kohno Yasuhito Ohkubo Takahiko Suzuki Kenichi Kitani |
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Institution: | aRadioisotope Research Institute, Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113, Japan;bDepartment of Radiopharmacy, Tohoku College of Pharmacy, Komatsushima 4-4-1, Aoba-ku, Sendai, 981, Japan |
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Abstract: | Transglutaminase (TGase) activity increased 2.5-fold at 6 h after treatment of rat hepatocytes with 117 nMhepatocyte growth factor (HGF). In the same manner, putrescine incorporation into proteins of cells occurred in HGF-treated cells but did not in those pretreated with monodansylcadaverine (MDC), a TGase inhibitor, even in the presence of HGF. These results suggest that HGF-induced TGase was active and catalyzed some cross-linkage reaction. Cycloheximide completely blocked the increase in TGase activity induced by HGF, suggesting that HGF stimulatedde novosynthesis of TGase within 6 h. Both 35S]methionine incorporation and Northern blotting analyses supported this possibility. Pretreatment of cells with MDC additionally increased HGF-induced DNA synthesis and the ratio of cells in S-phase. Similarly, TGase antisense oligonucleotide inhibitedde novosynthesis of TGase, resulting in increase in the ratio of S-phase cells in the presence of HGF. Analyses of cross-linking of HGF to the receptor indicated that the antisense oligonucleotide inhibited the downregulation of HGF receptor subsequent to HGF-addition. These results provide the first evidence for inducibility ofde novosynthesis of TGase by HGF and suggest that TGase negatively regulates the growth signal of HGF through the downregulation of receptor. |
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