期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：2
页码：844-849
DOI：10.1073/pnas.0909781107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：TGF-{beta}-activated kinase 1 (TAK1) is a MAP3K family member that activates NF-{kappa}B and JNK via Toll-like receptors and the receptors for IL-1, TNF-[α], and TGF-{beta}. Because the TAK1 downstream molecules NF-{kappa}B and JNK have opposite effects on cell death and carcinogenesis, the role of TAK1 in the liver is unpredictable. To address this issue, we generated hepatocyte-specific Tak1-deficient (Tak1{Delta}HEP) mice. The Tak1{Delta}HEP mice displayed spontaneous hepatocyte death, compensatory proliferation, inflammatory cell infiltration, and perisinusoidal fibrosis at age 1 month. Older Tak1{Delta}HEP mice developed multiple cancer nodules characterized by increased expression of fetal liver genes including [α]-fetoprotein. Cultures of primary hepatocytes deficient in Tak1 exhibited spontaneous cell death that was further increased in response to TNF-[α]. TNF-[α] increased caspase-3 activity but activated neither NF-{kappa}B nor JNK in Tak1-deficient hepatocytes. Genetic abrogation of TNF receptor type I (TNFRI) in Tak1{Delta}HEP mice reduced liver damage, inflammation, and fibrosis compared with unmodified Tak1{Delta}HEP mice. In conclusion, hepatocyte-specific deletion of TAK1 in mice resulted in spontaneous hepatocyte death, inflammation, fibrosis, and carcinogenesis that was partially mediated by TNFR signaling, indicating that TAK1 is an essential component for cellular homeostasis in the liver.
关键词：apoptosis ; JNK ; liver cancer ; NF-kB ; TNF-α
