期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 104, 期 1, 页码 139-144出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0601947103
关键词
G protein-coupled receptor; hepatocyte; IkB kinase; inflammation; ubiquitination
资金
- NCI NIH HHS [5K08 CA097986, P30 CA046592, K08 CA094920, K08 CA097986, 5P30 CA46592, R01 CA084064, 5K08 CA094920] Funding Source: Medline
Angiotensin II (Ang II) is a peptide hormone that, like many cytokines, acts as a proinflammatory agent and growth factor. After injury to the liver, the hormone assists in tissue repair by stimulating hepatocytes and hepatic stellate cells to synthesize extracellular matrix proteins and secrete secondary cytokines and by stimulating myofibroblasts to proliferate. However, under conditions of chronic liver injury, all of these effects conspire to promote pathologic liver fibrosis. Much of this effect of Ang III results from activation of the proinflammatory NF-kappa B transcription factor in response to stimulation of the type 1 Ang II receptor, a G protein-coupled receptor. Here, we characterize a previously undescribed signaling pathway mediating Ang II-dependent activation of NF-kappa B, which is composed of three principal proteins, CARMA3, Bcl10, and MALT1. Blocking the function of any of these proteins, through the use of either dominant-negative mutants, RNAi, or gene targeting, effectively abolishes Ang II-dependent NF-kappa B activation in hepatocytes. In addition, Bcl10(-/-) mice show defective hepatic cytokine production after Ang II treatment. Evidence also is presented that this pathway activates NF-kappa B through ubiquitination of IKK gamma, the regulatory subunit of the I kappa B kinase complex. These results elucidate a concrete series of molecular events that link ligand activation of the type 1 Ang II receptor to stimulation of the NF-kappa B transcription factor. These findings also uncover a function of the CARMA, Bcl10, and MALT1 proteins in cells outside the immune system.
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