{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T05:45:35Z","timestamp":1761630335082,"version":"3.30.0"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":5509,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2000,8]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>Transforming growth factor \u03b2 (TGF-\u03b2) initiates signaling through heteromeric complexes of transmembrane type I and type II serine\/threonine kinase receptors. Activated TGF-\u03b2 type I receptor phosphorylates receptor-regulated Smads (2 and 3). Antagonistic Smad 7 forms stable association with the activated TGF-\u03b2 type I receptor, blocking phosphorylation of receptor-regulated Smads. On the other hand, elevated serum concentration of TGF-\u03b2 along with resistance to its growth-inhibitory effect is commonly observed in human hepatocellular carcinoma (HCC) patients. In this study, we investigated the mechanisms of resistance to tumor-derived TGF-\u03b2 in human HCC and hepatoblastoma-derived cell lines, focusing on the roles of receptor-regulated Smads and antagonistic Smad 7. HuH-7 and HepG2 cells showed poor response to TGF-\u03b2-mediated growth inhibition. Because neutralization of TGF-\u03b2 in the medium or blockage of signal transduction pathway by inductions of dominant negative Smad 2\/3 resulted in a stimulation of cell growth, tumor-derived TGF-\u03b2 signal acts on cell growth negatively. However, Smad 7 induced by TGF-\u03b2 negatively regulated Smad 2 action and rendered most Smad 2 proteins in the cytoplasm. Taken together, these results indicate that endogenous TGF-\u03b2-mediated induction of Smad 7 results in a higher \u201cthreshold\u201d for the antiproliferative signals mediated by receptor-regulated Smads, and can be involved in reduced responsiveness to the cytokine in some human HCC cells.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1053\/jhep.2000.9145","type":"journal-article","created":{"date-parts":[[2004,3,19]],"date-time":"2004-03-19T22:03:01Z","timestamp":1079733781000},"page":"218-227","update-policy":"http:\/\/dx.doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":37,"title":["Regulatory mechanisms for transforming growth factor \u03b2 as an autocrine inhibitor in human hepatocellular carcinoma: Implications for roles of Smads in its growth"],"prefix":"10.1097","volume":"32","author":[{"given":"Koichi","family":"Matsuzaki","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masataka","family":"Date","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fukiko","family":"Furukawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiya","family":"Tahashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masanori","family":"Matsushita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasushi","family":"Sugano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noriyo","family":"Yamashiki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taichi","family":"Nakagawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshihito","family":"Seki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikio","family":"Nishizawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junichi","family":"Fujisawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyoichi","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"10.1053\/jhep.2000.9145-BIB1","first-page":"419","volume-title":"Handbook of Experimental Pharmacology","author":"Roberts","year":"1990","unstructured":". Peptide growth factors and their receptors. In: eds. Handbook of Experimental Pharmacology. Heidelberg: Springer-Verlag. 1990; 419-472."},{"key":"10.1053\/jhep.2000.9145-BIB2","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1146\/annurev.biochem.67.1.753","volume":"67","author":"Massagu\u00e9","year":"1998","journal-title":"Annu Rev Biochem"},{"key":"10.1053\/jhep.2000.9145-BIB3","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/370341a0","volume":"370","author":"Wrana","year":"1994","journal-title":"Nature"},{"key":"10.1053\/jhep.2000.9145-BIB4","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1016\/S0092-8674(00)81817-6","volume":"87","author":"Mac\u00edas-Silva","year":"1996","journal-title":"Cell"},{"key":"10.1053\/jhep.2000.9145-BIB5","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/383168a0","volume":"383","author":"Zhang","year":"1996","journal-title":"Nature"},{"key":"10.1053\/jhep.2000.9145-BIB6","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1038\/383832a0","volume":"383","author":"Lagna","year":"1996","journal-title":"Nature"},{"key":"10.1053\/jhep.2000.9145-BIB7","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/S0092-8674(00)81696-7","volume":"95","author":"Derynck","year":"1998","journal-title":"Cell"},{"key":"10.1053\/jhep.2000.9145-BIB8","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/S0092-8674(00)81556-1","volume":"100","author":"Wrana","year":"2000","journal-title":"Cell"},{"key":"10.1053\/jhep.2000.9145-BIB9","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1038\/39355","volume":"389","author":"Imamura","year":"1997","journal-title":"Nature"},{"key":"10.1053\/jhep.2000.9145-BIB10","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1101\/gad.12.2.186","volume":"12","author":"Hata","year":"1998","journal-title":"Genes Dev"},{"key":"10.1053\/jhep.2000.9145-BIB11","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1016\/S0092-8674(00)80303-7","volume":"89","author":"Hayashi","year":"1997","journal-title":"Cell"},{"key":"10.1053\/jhep.2000.9145-BIB12","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/39369","volume":"389","author":"Nakao","year":"1997","journal-title":"Nature"},{"key":"10.1053\/jhep.2000.9145-BIB13","doi-asserted-by":"crossref","first-page":"33412","DOI":"10.1074\/jbc.274.47.33412","volume":"274","author":"Nagarajan","year":"1999","journal-title":"J Biol Chem"},{"key":"10.1053\/jhep.2000.9145-BIB14","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1096\/fasebj.9.15.8529831","volume":"9","author":"Fausto","year":"1995","journal-title":"FASEB J"},{"key":"10.1053\/jhep.2000.9145-BIB15","first-page":"760","volume":"21","author":"Bedossa","year":"1995","journal-title":"Hepatology"},{"key":"10.1053\/jhep.2000.9145-BIB16","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1002\/1097-0142(19940501)73:9<2275::AID-CNCR2820730907>3.0.CO;2-T","volume":"73","author":"Shirai","year":"1994","journal-title":"Cancer"},{"key":"10.1053\/jhep.2000.9145-BIB17","first-page":"1394","volume":"60","author":"Matsuzaki","year":"2000","journal-title":"Cancer Res"},{"key":"10.1053\/jhep.2000.9145-BIB18","first-page":"1909","volume":"12","author":"Fan","year":"1996","journal-title":"Oncogene"},{"key":"10.1053\/jhep.2000.9145-BIB19","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/S0168-8278(98)80280-8","volume":"28","author":"Date","year":"1998","journal-title":"J Hepatol"},{"key":"10.1053\/jhep.2000.9145-BIB20","doi-asserted-by":"crossref","first-page":"9911","DOI":"10.1073\/pnas.86.24.9911","volume":"86","author":"Matsuzaki","year":"1989","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1053\/jhep.2000.9145-BIB21","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1046\/j.1365-2443.1998.00193.x","volume":"3","author":"Sakitani","year":"1998","journal-title":"Genes to Cells"},{"key":"10.1053\/jhep.2000.9145-BIB22","doi-asserted-by":"crossref","first-page":"6419","DOI":"10.1093\/nar\/17.15.6419","volume":"17","author":"Schreiber","year":"1989","journal-title":"Nucleic Acids Res"},{"key":"10.1053\/jhep.2000.9145-BIB23","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1038\/sj.bjc.6690339","volume":"80","author":"Matsushita","year":"1999","journal-title":"Br J Cancer"},{"key":"10.1053\/jhep.2000.9145-BIB24","doi-asserted-by":"crossref","first-page":"2199","DOI":"10.1002\/j.1460-2075.1995.tb07214.x","volume":"14","author":"Wieser","year":"1995","journal-title":"EMBO J"},{"key":"10.1053\/jhep.2000.9145-BIB25","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1016\/0092-8674(92)90395-S","volume":"71","author":"Wrana","year":"1992","journal-title":"Cell"},{"key":"10.1053\/jhep.2000.9145-BIB26","first-page":"367","volume":"1","author":"Arteaga","year":"1990","journal-title":"Cell Growth Differ"},{"key":"10.1053\/jhep.2000.9145-BIB27","first-page":"617","volume":"1","author":"Hafez","year":"1990","journal-title":"Cell Growth Differ"},{"key":"10.1053\/jhep.2000.9145-BIB28","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1083\/jcb.116.1.187","volume":"116","author":"Wu","year":"1992","journal-title":"J Cell Biol"},{"key":"10.1053\/jhep.2000.9145-BIB29","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1126\/science.7518616","volume":"265","author":"Wang","year":"1994","journal-title":"Science"},{"key":"10.1053\/jhep.2000.9145-BIB30","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/S0092-8674(00)81701-8","volume":"95","author":"Tsukazaki","year":"1998","journal-title":"Cell"},{"key":"10.1053\/jhep.2000.9145-BIB31","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/371257a0","volume":"371","author":"Hannon","year":"1994","journal-title":"Nature"},{"key":"10.1053\/jhep.2000.9145-BIB32","doi-asserted-by":"crossref","first-page":"5545","DOI":"10.1073\/pnas.92.12.5545","volume":"92","author":"Datto","year":"1995","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1053\/jhep.2000.9145-BIB33","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/27945","volume":"394","author":"Kurokawa","year":"1998","journal-title":"Nature"},{"key":"10.1053\/jhep.2000.9145-BIB34","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/S1097-2765(00)80201-4","volume":"4","author":"Sun","year":"1999","journal-title":"Mol Cell"},{"key":"10.1053\/jhep.2000.9145-BIB35","first-page":"1452","volume":"55","author":"Alexandrow","year":"1995","journal-title":"Cancer Res"},{"key":"10.1053\/jhep.2000.9145-BIB36","doi-asserted-by":"crossref","first-page":"5913","DOI":"10.1128\/MCB.19.9.5913","volume":"19","author":"Warner","year":"1999","journal-title":"Mol Cell Biol"},{"key":"10.1053\/jhep.2000.9145-BIB37","first-page":"407","volume":"149","author":"Santoni-Rugiu","year":"1996","journal-title":"Am J Pathol"},{"key":"10.1053\/jhep.2000.9145-BIB38","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1002\/(SICI)1097-0215(19990719)82:2<197::AID-IJC8>3.0.CO;2-V","volume":"82","author":"Korchynskyi","year":"1999","journal-title":"Int J Cancer"},{"key":"10.1053\/jhep.2000.9145-BIB39","first-page":"2731","volume":"59","author":"Brodin","year":"1999","journal-title":"Cancer Res"},{"key":"10.1053\/jhep.2000.9145-BIB40","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1093\/carcin\/15.8.1473","volume":"15","author":"Jirtle","year":"1994","journal-title":"Carcinogenesis"},{"key":"10.1053\/jhep.2000.9145-BIB41","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S0304-3835(97)00289-9","volume":"120","author":"Piao","year":"1997","journal-title":"Cancer Lett"},{"key":"10.1053\/jhep.2000.9145-BIB42","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1006\/bbrc.1996.0934","volume":"223","author":"Vincent","year":"1996","journal-title":"Biochem Biophys Res Commun"},{"key":"10.1053\/jhep.2000.9145-BIB43","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/sj.onc.1202279","volume":"18","author":"Salvucci","year":"1999","journal-title":"Oncogene"},{"key":"10.1053\/jhep.2000.9145-BIB44","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1002\/(SICI)1097-0215(19990611)81:6<851::AID-IJC2>3.0.CO;2-D","volume":"81","author":"Furuta","year":"1999","journal-title":"Int J Cancer"},{"key":"10.1053\/jhep.2000.9145-BIB45","first-page":"2527","volume":"56","author":"Schutte","year":"1996","journal-title":"Cancer Res"},{"key":"10.1053\/jhep.2000.9145-BIB46","doi-asserted-by":"crossref","first-page":"4879","DOI":"10.1038\/sj.onc.1202866","volume":"18","author":"Yakicier","year":"1999","journal-title":"Oncogene"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1053%2Fjhep.2000.9145","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-200008000-00009","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T11:28:57Z","timestamp":1733052537000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-200008000-00009"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,8]]},"references-count":46,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2000]]}},"URL":"https:\/\/doi.org\/10.1053\/jhep.2000.9145","relation":{},"ISSN":["0270-9139"],"issn-type":[{"type":"print","value":"0270-9139"}],"subject":[],"published":{"date-parts":[[2000,8]]}}}