Nopp140 Is a Mediator of the Protein Kinase a Signaling Pathway That Activates the Acute Phase Response Alpha(1)-Acid Glycoprotein Gene
Resource
JOURNAL OF BIOLOGICAL CHEMISTRY v.277 n.42 pp.39102-39111
Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Journal Volume
v.277
Journal Issue
n.42
Pages
39102-39111
Date Issued
2002
Date
2002
Author(s)
LEE, SHENG-CHUNG
Abstract
The acute phase response (APR) in liver during inflammation is one of the well known examples for elucidating the signaling pathways that lead to the combinatorial regulation of gene expression. The APR is exemplified by alpha(1)-acid glycoprotein gene (agp) expression. A number of transcription factors, including CCAAT/enhancer-binding protein beta (C/ EBPbeta), glucocorticoid receptor, cAMP- response element-binding protein (CREB), and Nopp140, are known to participate in its induction. The underlying mechanism of Nopp140 and other factors for regulating agp expression remains unclear. Here we demonstrate that protein kinase A (PKA )-dependent phosphorylation of Nopp140, together with C/EBPbeta, induces agp gene expression synergistically. The cooperative activation of the agp gene by Nopp140 and forskolin is sensitive to inhibition by PKI. Results from biochemical and functional characterizations of Nopp140 mutants defective in PKA phosphorylation sites suggest that PKA-dependent Nopp140 phosphorylation is important for its role in agp gene activation. Furthermore, maximal activation of the agp gene by PKA-phosphorylated Nopp 140 depends on the presence of CREB and C/EBPbeta. The participation of CREB in the activation is, however, independent of its PKA-mediated phosphorylation. In summary, we demonstrate the existence of a novel Nopp 140-mediated PKA signaling pathway that leads to the activation of agp, one of the major acute phase response genes.
Subjects
ELEMENT-BINDING PROTEIN
ALPHA-1-ACID GLYCOPROTEIN
C/EBP-BETA
TRANSCRIPTION FACTOR
SOMATOSTATIN GENE
PHOSPHOENOLPYRUVATE CARBOXYKINASE