Ester Sala1,2, Celia Vived1,2, Júlia Luna1,2, Noemí Alejandra Saavedra-Ávila1,2, Upasana Sengupta1,2, A Raúl Castaño3, Sabrina Villar-Pazos4,5, Laura Haba6, Joan Verdaguer1,2, Ana B Ropero7, Thomas Stratmann8, Javier Pizarro9,10,11, Manuel Vázquez-Carrera9,10,11, Angel Nadal4,12, Jill M Lahti5, Conchi Mora1,2. 1. Immunology Unit, Department of Experimental Medicine, Faculty of Medicine, University of Lleida, Lleida, Spain. 2. Institut de Recerca Biomèdica Lleida (IRB-LLeida), Lleida, Spain. 3. Departament of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona, Barcelona, Spain. 4. Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche, IDiBE, Universidad Miguel Hernandez, Elche, Spain. 5. Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN, United States. 6. Experimental Diabetes Laboratory, Institute for Biomedical Research August Pi i Sunyer (IDIBAPS), Barcelona, Spain. 7. Instituto de Bioingeniería, Universidad Miguel Hernández, Elche, Spain. 8. Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain. 9. Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain. 10. Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain. 11. Pediatric Research Institute, Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain. 12. Diabetes and Associated Metabolic Disorders CIBERDEM, Universidad Miguel Hernández de Elche, Elche, Spain.
Abstract
Background: Pancreatic islets are exposed to strong pro-apoptotic stimuli: inflammation and hyperglycemia, during the progression of the autoimmune diabetes (T1D). We found that the Cdk11(Cyclin Dependent Kinase 11) is downregulated by inflammation in the T1D prone NOD (non-obese diabetic) mouse model. The aim of this study is to determine the role of CDK11 in the pathogenesis of T1D and to assess the hierarchical relationship between CDK11 and Cyclin D3 in beta cell viability, since Cyclin D3, a natural ligand for CDK11, promotes beta cell viability and fitness in front of glucose. Methods: We studied T1D pathogenesis in NOD mice hemideficient for CDK11 (N-HTZ), and, in N-HTZ deficient for Cyclin D3 (K11HTZ-D3KO), in comparison to their respective controls (N-WT and K11WT-D3KO). Moreover, we exposed pancreatic islets to either pro-inflammatory cytokines in the presence of increasing glucose concentrations, or Thapsigargin, an Endoplasmic Reticulum (ER)-stress inducing agent, and assessed apoptotic events. The expression of key ER-stress markers (Chop, Atf4 and Bip) was also determined. Results: N-HTZ mice were significantly protected against T1D, and NS-HTZ pancreatic islets exhibited an impaired sensitivity to cytokine-induced apoptosis, regardless of glucose concentration. However, thapsigargin-induced apoptosis was not altered. Furthermore, CDK11 hemideficiency did not attenuate the exacerbation of T1D caused by Cyclin D3 deficiency. Conclusions: This study is the first to report that CDK11 is repressed in T1D as a protection mechanism against inflammation-induced apoptosis and suggests that CDK11 lies upstream Cyclin D3 signaling. We unveil the CDK11/Cyclin D3 tandem as a new potential intervention target in T1D.
Background: Pancreatic islets are exposed to strong pro-apoptotic stimuli: inflammation and hyperglycemia, during the progression of the autoimmune diabetes (T1D). We found that the Cdk11(Cyclin Dependent Kinase 11) is downregulated by inflammation in the T1D prone NOD (non-obese diabetic) mouse model. The aim of this study is to determine the role of CDK11 in the pathogenesis of T1D and to assess the hierarchical relationship between CDK11 and Cyclin D3 in beta cell viability, since Cyclin D3, a natural ligand for CDK11, promotes beta cell viability and fitness in front of glucose. Methods: We studied T1D pathogenesis in NOD mice hemideficient for CDK11 (N-HTZ), and, in N-HTZ deficient for Cyclin D3 (K11HTZ-D3KO), in comparison to their respective controls (N-WT and K11WT-D3KO). Moreover, we exposed pancreatic islets to either pro-inflammatory cytokines in the presence of increasing glucose concentrations, or Thapsigargin, an Endoplasmic Reticulum (ER)-stress inducing agent, and assessed apoptotic events. The expression of key ER-stress markers (Chop, Atf4 and Bip) was also determined. Results: N-HTZ mice were significantly protected against T1D, and NS-HTZ pancreatic islets exhibited an impaired sensitivity to cytokine-induced apoptosis, regardless of glucose concentration. However, thapsigargin-induced apoptosis was not altered. Furthermore, CDK11 hemideficiency did not attenuate the exacerbation of T1D caused by Cyclin D3 deficiency. Conclusions: This study is the first to report that CDK11 is repressed in T1D as a protection mechanism against inflammation-induced apoptosis and suggests that CDK11 lies upstream Cyclin D3 signaling. We unveil the CDK11/Cyclin D3 tandem as a new potential intervention target in T1D.
Authors: Erik W Wilker; Marcel A T M van Vugt; Steven A Artim; Paul H Huang; Christian P Petersen; H Christian Reinhardt; Yun Feng; Phillip A Sharp; Nahum Sonenberg; Forest M White; Michael B Yaffe Journal: Nature Date: 2007-03-15 Impact factor: 49.962