The Essential Role of the Crtc2-CREB Pathway in β Cell Function and Survival

FieldValue
dc.contributor.authorEberhard, Chandra
dc.date.accessioned2013-01-23T16:32:28Z
dc.date.available2013-07-23T10:00:04Z
dc.date.created2013
dc.date.issued2013
dc.identifier.urihttp://hdl.handle.net/10393/23705
dc.identifier.urihttp://dx.doi.org/10.20381/ruor-3136
dc.description.abstractImmunosuppressants that target the serine/threonine phosphatase calcineurin are commonly administered following organ transplantation. Their chronic use is associated with reduced insulin secretion and new onset diabetes in a subset of patients, suggestive of pancreatic β cell dysfunction. Calcineurin plays a critical role in the activation of CREB, a key transcription factor required for β cell function and survival. CREB activity in the islet is activated by glucose and cAMP, in large part due to activation of Crtc2, a critical coactivator for CREB. Previous studies have demonstrated that Crtc2 activation is dependent on dephosphorylation regulated by calcineurin. In this study, we sought to evaluate the impact of calcineurin-inhibiting immunosuppressants on Crtc2-CREB activation in the primary β cell. In addition, we further characterized the role and regulation of Crtc2 in the β cell. We demonstrate that Crtc2 is required for glucose dependent up-regulation of CREB target genes. The phosphatase calcineurin and kinase regulation by LKB1 contribute to the phosphorylation status of Crtc2 in the β cell. CsA and FK506 block glucose-dependent dephosphorylation and nuclear translocation of Crtc2. Overexpression of a constitutively active mutant of Crtc2 that cannot be phosphorylated at Ser171 and Ser275 enables CREB activity under conditions of calcineurin inhibition. Furthermore, β cells lacking Crtc2 display impaired glucose-stimulated insulin secretion and cell survival. Together, these results demonstrate that phosphorylation of Crtc2 plays a critical role in regulating CREB activity and contributes to β cell dysfunction and death caused by chronic immunosuppression.
dc.language.isoen
dc.publisherUniversité d'Ottawa / University of Ottawa
dc.subjectDiabetes
dc.subjectInsulin
dc.subjectCreb
dc.subjectCrtc2
dc.subjectCalcineurin
dc.subjectPhosphorylation
dc.subjectbeta cell
dc.titleThe Essential Role of the Crtc2-CREB Pathway in β Cell Function and Survival
dc.typeThesis
dc.faculty.departmentMédecine cellulaire et moléculaire / Cellular and Molecular Medicine
dc.contributor.supervisorScreaton, Robert
dc.embargo.terms6 months
dc.degree.nameMSc
dc.degree.levelmasters
dc.degree.disciplineMédecine / Medicine
thesis.degree.nameMSc
thesis.degree.levelMasters
thesis.degree.disciplineMédecine / Medicine
uottawa.departmentMédecine cellulaire et moléculaire / Cellular and Molecular Medicine
CollectionThèses, 2011 - // Theses, 2011 -

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