title: Npas4 Transcription Factor Expression Is Regulated by Calcium Signaling Pathways and Prevents Tacrolimus-induced Cytotoxicity in Pancreatic Beta Cells.
abstract: 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.
authors.affiliation: From the Diabetes Research Program, Child and Family Research Institute, Vancouver, British Columbia V5Z 4H4, Canada and the Department of Surgery and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada.
authors.forename: Thilo
authors.initials: T
authors.lastname: Speckmann
authors.affiliation: From the Diabetes Research Program, Child and Family Research Institute, Vancouver, British Columbia V5Z 4H4, Canada and the Department of Surgery and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada.
authors.forename: Paul V
authors.initials: PV
authors.lastname: Sabatini
authors.affiliation: From the Diabetes Research Program, Child and Family Research Institute, Vancouver, British Columbia V5Z 4H4, Canada and the Department of Surgery and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada.
authors.forename: Cuilan
authors.initials: C
authors.lastname: Nian
authors.affiliation: From the Diabetes Research Program, Child and Family Research Institute, Vancouver, British Columbia V5Z 4H4, Canada and.
authors.forename: Riley G
authors.initials: RG
authors.lastname: Smith
authors.affiliation: From the Diabetes Research Program, Child and Family Research Institute, Vancouver, British Columbia V5Z 4H4, Canada and the Department of Surgery and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada francis.lynn@ubc.ca.
authors.forename: Francis C
authors.identifier: http://orcid.org/0000-0001-9318-1063
authors.initials: FC
authors.lastname: Lynn
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D003603:Cytotoxins / Q000009:adverse effects* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016559:Tacrolimus / Q000009:adverse effects* / Q000494:pharmacology; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019703:Calcineurin; D003603:Cytotoxins; D046988:Proteasome Endopeptidase Complex; D051057:Proto-Oncogene Proteins c-akt; D016559:Tacrolimus; D025801:Ubiquitin; C533005:Npas4 protein, mouse
keywords: MIN6 cell; Npas4; activity-regulated; beta cell; calcineurin; calcium signaling; insulin secretion; pancreatic islet; transcription factor