Nopp140 is a mediator of the protein kinase A signaling pathway that activates the acute phase response alpha1-acid glycoprotein gene.
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 Nopp140 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 Nopp140-mediated PKA signaling pathway that leads to the activation of agp, one of the major acute phase response genes.
Chiu
Chi-Ming
CM
Institute of Molecular Medicine and Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Tsay
Yeou-Guang
YG
Chang
Ching-Jin
CJ
Lee
Sheng-Chung
SC
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism* / Q000502:physiology*; D009961:Orosomucoid / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism* / Q000502:physiology*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
D022782:CCAAT-Enhancer-Binding Protein-beta; D017362:Cyclic AMP Response Element-Binding Protein; D018076:DNA, Complementary; C075564:NOLC1 protein, human; D009687:Nuclear Proteins; D009961:Orosomucoid; D010750:Phosphoproteins; D011994:Recombinant Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases