Linked Life Data

21488081

Source:http://linkedlifedata.com/resource/pubmed/id/21488081

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2011-6-28
pubmed:abstractText
The stress-activated mitogen-activated protein kinases (MAPKs), c-Jun NH2-terminal kinase (JNK), and p38 have been implicated in hepatocarcinogenesis. Although the many interrelated functions of JNK and p38 are precisely regulated by upstream signaling molecules, little is known about upstream regulators. We investigated the role of apoptosis signal-regulating kinase 1 (ASK1), a major player in the regulation of JNK and p38 activities, in hepatocarcinogenesis using a mouse hepatocellular carcinoma (HCC) model. ASK1-deficient (ASK1(-/-) ) and wildtype (WT) mice were treated with diethylnitrosamine on postnatal day 14. Strikingly, after 7 months, approximately three times as many tumors developed in ASK1(-/-) mice as in WT mice. Although JNK and p38 activation were attenuated in ASK1(-/-) HCCs relative to WT HCCs, cell proliferation was comparable in HCCs from both types of mice. On the other hand, both cancer cell apoptosis and hyperphosphorylation of BimEL, a proapoptotic Bcl-2 family member, were suppressed in the ASK1(-/-) HCCs. ASK1(-/-) mice showed remarkable resistance to Fas-induced hepatocyte apoptosis in vivo, probably because of attenuated JNK-mediated BimEL phosphorylation and mitochondrial apoptotic pathway activation. The reintroduction of ASK1 to ASK1(-/-) mouse liver using an adenoviral vector restored Fas-induced hepatocyte death and phosphorylation of JNK and BimEL. Similar findings were obtained in tumor necrosis factor alpha-induced hepatocyte apoptosis. Furthermore, ASK1 was involved in DNA damage-induced p21 up-regulation through a p38 pathway. CONCLUSION: ASK1 is involved in death receptor-mediated apoptosis and DNA-damage response by way of stress-activated MAPK in the liver, and thus acts as a tumor suppressor in hepatocarcinogenesis. This study provides new insight into the regulation of stress- activated MAPK signaling in hepatocarcinogenesis.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
1527-3350
pubmed:author
pubmed:copyrightInfo
Copyright © 2011 American Association for the Study of Liver Diseases.
pubmed:issnType
Electronic
pubmed:volume
54
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
185-95
pubmed:meshHeading
pubmed-meshheading:21488081-Animals, pubmed-meshheading:21488081-Apoptosis, pubmed-meshheading:21488081-Apoptosis Regulatory Proteins, pubmed-meshheading:21488081-Carcinoma, Hepatocellular, pubmed-meshheading:21488081-Cell Proliferation, pubmed-meshheading:21488081-Diethylnitrosamine, pubmed-meshheading:21488081-Disease Models, Animal, pubmed-meshheading:21488081-Hepatocytes, pubmed-meshheading:21488081-Liver Neoplasms, pubmed-meshheading:21488081-MAP Kinase Kinase 4, pubmed-meshheading:21488081-MAP Kinase Kinase Kinase 5, pubmed-meshheading:21488081-Male, pubmed-meshheading:21488081-Membrane Proteins, pubmed-meshheading:21488081-Mice, pubmed-meshheading:21488081-Mice, Knockout, pubmed-meshheading:21488081-Mitogen-Activated Protein Kinases, pubmed-meshheading:21488081-Proto-Oncogene Proteins, pubmed-meshheading:21488081-Signal Transduction, pubmed-meshheading:21488081-Stress, Physiological, pubmed-meshheading:21488081-p38 Mitogen-Activated Protein Kinases
pubmed:year
2011
pubmed:articleTitle
Apoptosis signal-regulating kinase 1 inhibits hepatocarcinogenesis by controlling the tumor-suppressing function of stress-activated mitogen-activated protein kinase.
pubmed:affiliation
Department of Gastroenterology, University of Tokyo, Tokyo, Japan.
pubmed:publicationType
Journal Article