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  • Title: Angiotensin II induces nuclear factor (NF)-kappaB1 isoforms to bind the angiotensinogen gene acute-phase response element: a stimulus-specific pathway for NF-kappaB activation.
    Author: Jamaluddin M, Meng T, Sun J, Boldogh I, Han Y, Brasier AR.
    Journal: Mol Endocrinol; 2000 Jan; 14(1):99-113. PubMed ID: 10628750.
    Abstract:
    The vasopressor angiotensin II (AII) activates transcriptional expression of its precursor, angiotensinogen. This biological "positive feedback loop" occurs through an angiotensin receptor-coupled pathway that activates a multihormone-responsive enhancer of the angiotensinogen promoter, termed the acute-phase response element (APRE). Previously, we showed that the APRE is a cytokine [tumor necrosis factor-alpha (TNFalpha)]- inducible enhancer by binding the heterodimeric nuclear factor-kappaB (NF-kappaB) complex Rel A x NF-kappaB1. Here, we compare the mechanism for NF-kappaB activation by the AII agonist, Sar1 AII, with TNFalpha in HepG2 hepatocytes. Although Sar1 AII and TNFalpha both rapidly activate APRE-driven transcription within 3 h of treatment, the pattern of inducible NF-kappaB binding activity in electrophoretic mobility shift assay is distinct. In contrast to the TNFalpha mechanism, which strongly induces Rel A x NF-kappaB1 binding, Sar1 AII selectively activates a heterogenous pattern of NF-kappaB1 binding. Using a two-step microaffinity DNA binding assay, we observe that Sar1 AII recruits 50-, 56-, and 96-kDa NF-kappaB1 isoforms to bind the APRE. Binding of all three NF-kappaB1 isoforms occurs independently of changes in their nuclear abundance or proteolysis of cytoplasmic IkappaB inhibitors. Phorbol ester-sensitive protein kinase C (PKC) isoforms are required because PKC down-regulation completely blocks AII-inducible transcription and inducible NF-kappaB1 binding. We conclude that AII stimulates the NF-kappaB transcription factor pathway by activating latent DNA-binding activity of NF-kappaB subunits through a phorbol ester-sensitive (PKC-dependent) mechanism.
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