Research Papers: Pathology:

i3 signaling is associated with sexual dimorphic expression of the clock-controlled output gene Dbp in murine liver

Madhurendra Singh, Laura Bergmann, Alexander Lang, Katja Pexa, Fabian Kuck, Dennis Stibane, Linda Janke, Hakima Ezzahoini, Antje Lindecke, Constanze Wiek, Helmut Hanenberg, Karl Köhrer, Charlotte von Gall, Hans Reinke and Roland P. Piekorz _

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Oncotarget. 2018; 9:30213-30224. https://doi.org/10.18632/oncotarget.25727

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Madhurendra Singh1,8, Laura Bergmann1, Alexander Lang1, Katja Pexa1, Fabian Kuck1, Dennis Stibane1, Linda Janke5, Hakima Ezzahoini1, Antje Lindecke2, Constanze Wiek3, Helmut Hanenberg3,7, Karl Köhrer2, Charlotte von Gall4, Hans Reinke5,6 and Roland P. Piekorz1

1Institut für Biochemie und Molekularbiologie II, Medizinische Fakultät der Heinrich-Heine-Universität, Düsseldorf, Germany

2Biologisch-Medizinisches Forschungszentrum (BMFZ), Medizinische Fakultät der Heinrich-Heine-Universität, Düsseldorf, Germany

3Hals-Nasen-Ohren-Klinik, Medizinische Fakultät der Heinrich-Heine-Universität, Düsseldorf, Germany

4Institut für Anatomie II, Medizinische Fakultät der Heinrich-Heine-Universität, Düsseldorf, Germany

5Institut für Klinische Chemie und Laboratoriumsmedizin, Medizinische Fakultät der Heinrich-Heine-Universität, Düsseldorf, Germany

6IUF – Leibniz Institut für Umweltmedizinische Forschung, Düsseldorf, Germany

7Klinik für Kinderheilkunde III, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany

8Current address: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden

Correspondence to:

Roland P. Piekorz, email: [email protected]

Keywords: circadian regulation; galphai3/GNAI3; CREB; cytochrome P450; albumin D-box binding protein; Pathology

Received: February 07, 2017     Accepted: June 14, 2018     Published: July 13, 2018


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.

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