Source:http://linkedlifedata.com/resource/pubmed/id/19418558
Switch to
Predicate | Object |
---|---|
rdf:type | |
lifeskim:mentions | |
pubmed:issue |
6
|
pubmed:dateCreated |
2009-6-3
|
pubmed:abstractText |
Transforming growth factor beta (TGF-beta) signaling involves both tumor-suppression and oncogenesis. TGF-beta activates the TGF-beta type I receptor (TbetaRI) and c-Jun N-terminal kinase (JNK), which differentially phosphorylate the mediator Smad3 to become COOH-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). TbetaRI-dependent pSmad3C transmits a tumor-suppressive TGF-beta signal, while JNK-dependent pSmad3L promotes carcinogenesis in human chronic liver disorders. The aim of this study is to elucidate how SP600125, a JNK inhibitor, affected rat hepatocellular carcinoma (HCC) development, while focusing on the domain-specific phosphorylation of Smad3. The rats received subcutaneous injections of either SP600125 or vehicle 11 times weekly together with 100 ppm N-diethylnitrosamine (DEN) administration for 56 days and were sacrificed in order to evaluate HCC development 28 days after the last DEN administration. The number of tumor nodules greater than 3 mm in diameter and the liver weight/body weight ratio were significantly lower in the SP600125-treated rats than those in the vehicle-treated rats (7.9 +/- 0.8 versus 17.7 +/- 0.9: P < 0.001; 6.3 +/- 1.2 versus 7.1 +/- 0.2%: P < 0.05). SP600125 significantly prolonged the median survival time in rats with DEN-induced HCC (113 versus 97 days: log-rank P = 0.0018). JNK/pSmad3L/c-Myc was enhanced in the rat hepatocytes exposed to DEN. However, TbetaRI/pSmad3C/p21(WAF1) was impaired as DEN-induced HCC developed and progressed. The specific inhibition of JNK activity by SP600125 suppressed pSmad3L/c-Myc in the damaged hepatocytes and enhanced pSmad3C/p21(WAF1), acting as a tumor suppressor in normal hepatocytes. CONCLUSION: Administration of SP600125 to DEN-treated rats shifted hepatocytic Smad3-mediated signal from oncogenesis to tumor suppression, thus suggesting that JNK could be a therapeutic target of human HCC development and progression.
|
pubmed:language |
eng
|
pubmed:journal | |
pubmed:citationSubset |
IM
|
pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Anthracenes,
http://linkedlifedata.com/resource/pubmed/chemical/JNK Mitogen-Activated Protein...,
http://linkedlifedata.com/resource/pubmed/chemical/Madh3 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Smad3 Protein,
http://linkedlifedata.com/resource/pubmed/chemical/anthra(1,9-cd)pyrazol-6(2H)-one
|
pubmed:status |
MEDLINE
|
pubmed:month |
Jun
|
pubmed:issn |
1527-3350
|
pubmed:author |
pubmed-author:AsechiHiroyukiH,
pubmed-author:COXP JPJ,
pubmed-author:HatanoEtsuroE,
pubmed-author:KitamuraKojiK,
pubmed-author:MatsuzakiKoichiK,
pubmed-author:MurataMikiM,
pubmed-author:NagataHiromitsuH,
pubmed-author:NaritaMasatoM,
pubmed-author:TadaMasaharuM,
pubmed-author:TamakiNobuyukiN,
pubmed-author:UemotoShinjiS,
pubmed-author:YagiShintaroS,
pubmed-author:YanagidaAtsukoA
|
pubmed:issnType |
Electronic
|
pubmed:volume |
49
|
pubmed:owner |
NLM
|
pubmed:authorsComplete |
Y
|
pubmed:pagination |
1944-53
|
pubmed:dateRevised |
2009-11-19
|
pubmed:meshHeading |
pubmed-meshheading:19418558-Animals,
pubmed-meshheading:19418558-Anthracenes,
pubmed-meshheading:19418558-Carcinoma, Hepatocellular,
pubmed-meshheading:19418558-Genes, Tumor Suppressor,
pubmed-meshheading:19418558-JNK Mitogen-Activated Protein Kinases,
pubmed-meshheading:19418558-Liver Neoplasms,
pubmed-meshheading:19418558-Male,
pubmed-meshheading:19418558-Rats,
pubmed-meshheading:19418558-Rats, Wistar,
pubmed-meshheading:19418558-Signal Transduction,
pubmed-meshheading:19418558-Smad3 Protein
|
pubmed:year |
2009
|
pubmed:articleTitle |
Inhibition of c-Jun NH2-terminal kinase switches Smad3 signaling from oncogenesis to tumor- suppression in rat hepatocellular carcinoma.
|
pubmed:affiliation |
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
|
pubmed:publicationType |
Journal Article
|