التفاصيل البيبلوغرافية
| العنوان: |
Suppressor of Cytokine Signaling-3 Is a Glucagon-inducible Inhibitor of PKA Activity and Gluconeogenic Gene Expression in Hepatocytes. |
| المؤلفون: |
Gaudy, Allison M.1, Clementi, Alicia H.2, Campbell, Jean S.3, Smrcka, Alan V.1, Mooney, Robert A.2 RobertMooney@urmc.rochester.edu |
| المصدر: |
Journal of Biological Chemistry. 12/31/2010, Vol. 285 Issue 53, p41356-41365. 10p. |
| مصطلحات موضوعية: |
*LIVER cells, *CELLULAR immunity, *MESSENGER RNA, *GENE expression, *GENE expression in plants |
| مستخلص: |
SOCS3 is a cytokine-inducible negative regulator of cytokine receptor signaling. Recently, SOCS3 was shown to be induced by a cAMP-dependent pathway involving exchange protein directly activated by cAMP (Epac). We observed in livers of fasted mice that Socs3 mRNA was increased 4-fold compared with refed mice, suggesting a physiologic role for SOCS3 in the fasted state that may involve glucagon and Epac. Treating primary hepatocytes with glucagon resulted in a 4-fold increase in Socs3 mRNA levels. The Epac-selective cAMP analog 8-4-(chlorophenylthio)-2'-O-methyladenosine-3',5'-monophosphate, acetoxymethyl ester (cpTOME) increased Socs3 expression comparably. In gain-of-function studies, adenoviral expression of SOCS3 in primary hepatocytes caused a 50% decrease in 8-br-cAMP-dependent PKA phosphorylation of the transcription factor CREB. Induction of the gluconeogenic genes Ppargc1a, Pck1, and G6pc by glucagon or 8-br-cAMP was suppressed nearly 50%. In loss-of-function studies, hepatocytes from liver-specific SOCS3 knock-out mice responded to 8-br-cAMP with a 200% greater increase in Ppargc1a and Pck1 expression, and a 30% increase in G6pc expression, relative to wild-type cells. Suppression of SOCS3 by shRNA in hepatocytes resulted in a 60% increase in cAMP-dependent G6pc and Pck1 expression relative to control cells. SOCS3 expression also inhibited cAMP-dependent phosphorylation of the IP3 receptor but did not inhibit nuclear localization of the catalytic subunit of PKA. Using an in vitro kinase assay, cAMP-dependent PKA activity was reduced by 80% in hepatocytes expressing ectopic SOCS3. These data indicate that cAMP activates both the PKA and Epac pathways with induction of SOCS3 by the Epac pathway negatively regulating the PKA pathway. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
Academic Search Index |
Full Text Finder