Please use this identifier to cite or link to this item: doi:10.22028/D291-42287
Title: CK2 activity is crucial for proper glucagon expression
Author(s): Ampofo, Emmanuel
Pack, Mandy
Wrublewsky, Selina
Boewe, Anne S.
Spigelman, Aliya F.
Koch, Hanna
MacDonald, Patrick E.
Laschke, Matthias W.
Montenarh, Mathias
Götz, Claudia
Language: English
Title: Diabetologia
Volume: 67
Issue: 7
Pages: 1368-1385
Publisher/Platform: Springer Nature
Year of Publication: 2024
Free key words: Glucagon
Glucose homeostasis
Pancreatic alpha cells
PDX1
Protein kinase CK2
DDC notations: 610 Medicine and health
Publikation type: Journal Article
Abstract: Aims/hypothesis Protein kinase CK2 acts as a negative regulator of insulin expression in pancreatic beta cells. This action is mainly mediated by phosphorylation of the transcription factor pancreatic and duodenal homeobox protein 1 (PDX1). In pancreatic alpha cells, PDX1 acts in a reciprocal fashion on glucagon (GCG) expression. Therefore, we hypothesised that CK2 might positively regulate GCG expression in pancreatic alpha cells. Methods We suppressed CK2 kinase activity in αTC1 cells by two pharmacological inhibitors and by the CRISPR/Cas9 technique. Subsequently, we analysed GCG expression and secretion by real-time quantitative RT-PCR, western blot, luciferase assay, ELISA and DNA pull-down assays. We additionally studied paracrine efects on GCG secretion in pseudoislets, isolated murine islets and human islets. In vivo, we examined the efect of CK2 inhibition on blood glucose levels by systemic and alpha cell-specifc CK2 inhibition. Results We found that CK2 downregulation reduces GCG secretion in the murine alpha cell line αTC1 (e.g. from 1094±124 ng/l to 459±110 ng/l) by the use of the CK2-inhibitor SGC-CK2-1. This was due to a marked decrease in Gcg gene expression through alteration of the binding of paired box protein 6 (PAX6) and transcription factor MafB to the Gcg promoter. The analysis of the underlying mechanisms revealed that both transcription factors are displaced by PDX1. Ex vivo experiments in isolated murine islets and pseudoislets further demonstrated that CK2-mediated reduction in GCG secretion was only slightly afected by the higher insulin secretion after CK2 inhibition. The kidney capsule transplantation model showed the signifcance of CK2 for GCG expression and secretion in vivo. Finally, CK2 downregulation also reduced the GCG secretion in islets isolated from humans. Conclusions/interpretation These novel fndings not only indicate an important function of protein kinase CK2 for proper GCG expression but also demonstrate that CK2 may be a promising target for the development of novel glucose-lowering drugs.
DOI of the first publication: 10.1007/s00125-024-06128-1
URL of the first publication: https://link.springer.com/article/10.1007/s00125-024-06128-1
Link to this record: urn:nbn:de:bsz:291--ds-422876
hdl:20.500.11880/37956
http://dx.doi.org/10.22028/D291-42287
ISSN: 1432-0428
0012-186X
Date of registration: 27-Jun-2024
Description of the related object: Supplementary Information
Related object: https://static-content.springer.com/esm/art%3A10.1007%2Fs00125-024-06128-1/MediaObjects/125_2024_6128_MOESM1_ESM.pdf
Faculty: M - Medizinische Fakultät
Department: M - Chirurgie
M - Medizinische Biochemie und Molekularbiologie
Professorship: M - Prof. Dr. Robert Ernst
M - Prof. Dr. Michael D. Menger
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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