Gα
| Autor: | Karl Köhrer, Hans Reinke, Helmut Hanenberg, Charlotte von Gall, Katja Pexa, Roland P. Piekorz, Dennis Stibane, Madhurendra Singh, Constanze Wiek, Hakima Ezzahoini, Antje Lindecke, Alexander Lang, Fabian Kuck, Linda Janke, Laura Bergmann |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
CAMP Responsive Element Binding Protein biology CREB cytochrome P450 Chemistry Binding protein circadian regulation Research Paper: Pathology galphai3/GNAI3 Cell biology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology albumin D-box binding protein Gene expression Pathology biology.protein Signal transduction Transcription factor Gene 030217 neurology & neurosurgery PER1 |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | The albumin D-box binding protein (DBP) is a member of the PAR bZip (proline and acidic amino acid-rich basic leucine zipper) transcription factor family and functions as important regulator of circadian core and output gene expression. Gene expression of DBP itself is under the control of E-box-dependent binding by the Bmal1-Clock heterodimer and CRE-dependent binding by the cAMP responsive element binding protein (CREB). However, the signaling mechanism mediating CREB-dependent regulation of DBP expression in the peripheral clock remains elusive. In this study, we examined the role of the GPCR (G-protein-coupled receptor)/Gαi3 (Galphai3) controlled cAMP-CREB signaling pathway in the regulation of hepatic expression of core clock and clock-regulated genes, including Dbp. Analysis of circadian gene expression revealed that rhythmicity of hepatic transcript levels of the majority of core clock (including Per1) and clock-regulated genes were not affected by Gαi3 deficiency. Consistently, the period length of primary Gαi3 deficient tail fibroblasts expressing a Bmal1-Luciferase reporter was not affected. Interestingly, however, Gαi3 deficient female but not male mice showed a tendentiously increased activation of CREB (nuclear pSer133-CREB) accompanied by an advanced peak in Dbp gene expression and elevated mRNA levels of the cytochrome P450 family member Cyp3a11, a target gene of DBP. Accordingly, selective inhibition of CREB led to a strongly decreased expression of DBP and CYP3A4 (human Cyp3a11 homologue) in HepG2 liver cells. In summary, our data suggest that the Gαi3-pCREB signalling pathway functions as a regulator of sexual-dimorphic expression of DBP and its xenobiotic target enzymes Cyp3a11/CYP3A4. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|