Npas4 Transcription Factor Expression Is Regulated by Calcium Signaling Pathways and Prevents Tacrolimus-induced Cytotoxicity in Pancreatic Beta Cells
| Autor: | Riley G. Smith, Thilo Speckmann, Paul V. Sabatini, Francis C. Lynn, Cuilan Nian |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Proteasome Endopeptidase Complex 030209 endocrinology & metabolism Biology Biochemistry Tacrolimus Mice 03 medical and health sciences 0302 clinical medicine Insulin-Secreting Cells Gene expression Basic Helix-Loop-Helix Transcription Factors Animals Gene Regulation Calcium Signaling Protein kinase A Molecular Biology Protein kinase B Transcription factor Calcium signaling Cytotoxins Protein Stability Ubiquitin Calcineurin Cell Biology Cell biology 030104 developmental biology Gene Expression Regulation Cancer research Beta cell Signal transduction Proto-Oncogene Proteins c-akt |
| Zdroj: | Journal of Biological Chemistry. 291:2682-2695 |
| ISSN: | 0021-9258 |
| Popis: | Cytosolic calcium influx activates signaling pathways known to support pancreatic beta cell function and survival by modulating gene expression. Impaired calcium signaling leads to decreased beta cell mass and diabetes. To appreciate the causes of these cytotoxic perturbations, a more detailed understanding of the relevant signaling pathways and their respective gene targets is required. In this study, we examined the calcium-induced expression of the cytoprotective beta cell transcription factor Npas4. Pharmacological inhibition implicated the calcineurin, Akt/protein kinase B, and Ca(2+)/calmodulin-dependent protein kinase signaling pathways in the regulation of Npas4 transcription and translation. Both Npas4 mRNA and protein had high turnover rates, and, at the protein level, degradation was mediated via the ubiquitin-proteasome pathway. Finally, beta cell cytotoxicity of the calcineurin inhibitor and immunosuppressant tacrolimus (FK-506) was prevented by Npas4 overexpression. These results delineate the pathways regulating Npas4 expression and stability and demonstrate its importance in clinical settings such as islet transplantation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|