In Vivo Conditional Pax4 Overexpression in Mature Islet β-Cells Prevents Stress-Induced Hyperglycemia in Mice
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| Titel: | In Vivo Conditional Pax4 Overexpression in Mature Islet β-Cells Prevents Stress-Induced Hyperglycemia in Mice |
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| Autoren: | Hu He, Kai Hui, Lorenzo, Petra I, Brun, Thierry, Jimenez Moreno, Carmen M, Aeberhard, Deborah, Vallejo Ortega, Jorge, Cornu, Marion, Thorel, Fabrizio, Gjinovci, Asllan, Thorens, Bernard, Herrera, Pedro Luis, Meda, Paolo, Wollheim, Claes, Gauthier, Benoît |
| Weitere Verfasser: | European Commission, Swiss National Science Foundation, Juvenile Diabetes Research Foundation International, National Institutes of Health (US), Novo Nordisk Foundation, Junta de Andalucía, Fundación Progreso y Salud, Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| Quelle: | Diabetes Digital.CSIC. Repositorio Institucional del CSIC instname Consejo Superior de Investigaciones Científicas (CSIC) Diabetes; Vol 60 Diabetes, Vol. 60, No 6 (2011) pp. 1705-15 Diabetes, vol. 60, no. 6, pp. 1705-1715 |
| Verlagsinformationen: | American Diabetes Association, 2011. |
| Publikationsjahr: | 2011 |
| Schlagwörter: | 576.5, 0301 basic medicine, Apoptosis/genetics/physiology, Maf Transcription Factors, Large, Maf Transcription Factors, Large/genetics/metabolism, Immunoblotting, Streptozocin/toxicity, Apoptosis, Mice, Transgenic, Polymerase Chain Reaction, Streptozocin, Proto-Oncogene Proteins c-myc, Mice, 03 medical and health sciences, Stress, Physiological/physiology, Stress, Physiological, Insulin-Secreting Cells, Proto-Oncogene Proteins c-myc/genetics/metabolism, Glucose Transporter Type 2/genetics/metabolism, Animals, Insulin, Paired Box Transcription Factors, ddc:576.5, Cyclin-Dependent Kinase 4/genetics/metabolism, Homeodomain Proteins/genetics/metabolism, ddc:612, Proto-Oncogene Proteins c-bcl-2/genetics/metabolism, Hyperglycemia/chemically induced/metabolism/prevention & control, Glucose Transporter Type 2, Homeodomain Proteins, Insulin/genetics/metabolism, 0303 health sciences, Apoptosis/genetics, Apoptosis/physiology, Cyclin-Dependent Kinase 4/genetics, Cyclin-Dependent Kinase 4/metabolism, Cytochromes c/genetics, Cytochromes c/metabolism, Glucose Transporter Type 2/genetics, Glucose Transporter Type 2/metabolism, Homeodomain Proteins/genetics, Homeodomain Proteins/metabolism, Hyperglycemia/chemically induced, Hyperglycemia/metabolism, Immunohistochemistry, Insulin/genetics, Insulin/metabolism, Insulin-Secreting Cells/cytology, Insulin-Secreting Cells/metabolism, Maf Transcription Factors, Large/genetics, Maf Transcription Factors, Large/metabolism, Paired Box Transcription Factors/genetics, Paired Box Transcription Factors/metabolism, Proto-Oncogene Proteins c-bcl-2/genetics, Proto-Oncogene Proteins c-bcl-2/metabolism, Proto-Oncogene Proteins c-myc/genetics, Proto-Oncogene Proteins c-myc/metabolism, Cyclin-Dependent Kinase 4, Cytochromes c, 3. Good health, Paired Box Transcription Factors/genetics/metabolism, Islet Studies, Proto-Oncogene Proteins c-bcl-2, Hyperglycemia, Insulin-Secreting Cells/cytology/metabolism, Cytochromes c/genetics/metabolism |
| Beschreibung: | OBJECTIVE To establish the role of the transcription factor Pax4 in pancreatic islet expansion and survival in response to physiological stress and its impact on glucose metabolism, we generated transgenic mice conditionally and selectively overexpressing Pax4 or a diabetes-linked mutant variant (Pax4R129W) in β-cells. RESEARCH DESIGN AND METHODS Glucose homeostasis and β-cell death and proliferation were assessed in Pax4- or Pax4R129W-overexpressing transgenic animals challenged with or without streptozotocin. Isolated transgenic islets were also exposed to cytokines, and apoptosis was evaluated by DNA fragmentation or cytochrome C release. The expression profiles of proliferation and apoptotic genes and β-cell markers were studied by immunohistochemistry and quantitative RT-PCR. RESULTS Pax4 but not Pax4R129W protected animals against streptozotocin-induced hyperglycemia and isolated islets from cytokine-mediated β-cell apoptosis. Cytochrome C release was abrogated in Pax4 islets treated with cytokines. Interleukin-1β transcript levels were suppressed in Pax4 islets, whereas they were increased along with NOS2 in Pax4R129W islets. Bcl-2, Cdk4, and c-myc expression levels were increased in Pax4 islets while MafA, insulin, and GLUT2 transcript levels were suppressed in both animal models. Long-term Pax4 expression promoted proliferation of a Pdx1-positive cell subpopulation while impeding insulin secretion. Suppression of Pax4 rescued this defect with a concomitant increase in pancreatic insulin content. CONCLUSIONS Pax4 protects adult islets from stress-induced apoptosis by suppressing selective nuclear factor-κB target genes while increasing Bcl-2 levels. Furthermore, it promotes dedifferentiation and proliferation of β-cells through MafA repression, with a concomitant increase in Cdk4 and c-myc expression. |
| Publikationsart: | Article Other literature type |
| Dateibeschreibung: | application/pdf |
| Sprache: | English |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db10-1102 |
| DOI: | 10.13039/100000901 |
| DOI: | 10.13039/501100000780 |
| DOI: | 10.13039/100000002 |
| DOI: | 10.13039/501100011011 |
| Zugangs-URL: | http://diabetes.diabetesjournals.org/content/60/6/1705.full.pdf https://pubmed.ncbi.nlm.nih.gov/21521872 http://hdl.handle.net/10261/51150 https://archive-ouverte.unige.ch/unige:25005/ATTACHMENT01 https://serval.unil.ch/resource/serval:BIB_0D2579782668.P001/REF.pdf https://diabetes.diabetesjournals.org/content/early/2011/04/22/db10-1102.article-info https://www.ncbi.nlm.nih.gov/pubmed/21521872 http://digital.csic.es/bitstream/10261/51150/4/HUHE_PAX4_REVISED_DIABETES_2011.pdf https://diabetes.diabetesjournals.org/content/60/6/1705.supplemental https://archive-ouverte.unige.ch/unige:25005 https://serval.unil.ch/resource/serval:BIB_0D2579782668.P001/REF.pdf http://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:serval-BIB_0D25797826684 https://serval.unil.ch/notice/serval:BIB_0D2579782668 |
| Rights: | CC BY NC ND |
| Dokumentencode: | edsair.doi.dedup.....b43996fb6545ff2cf025baf9d4ab3104 |
| Datenbank: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstract: | OBJECTIVE To establish the role of the transcription factor Pax4 in pancreatic islet expansion and survival in response to physiological stress and its impact on glucose metabolism, we generated transgenic mice conditionally and selectively overexpressing Pax4 or a diabetes-linked mutant variant (Pax4R129W) in β-cells. RESEARCH DESIGN AND METHODS Glucose homeostasis and β-cell death and proliferation were assessed in Pax4- or Pax4R129W-overexpressing transgenic animals challenged with or without streptozotocin. Isolated transgenic islets were also exposed to cytokines, and apoptosis was evaluated by DNA fragmentation or cytochrome C release. The expression profiles of proliferation and apoptotic genes and β-cell markers were studied by immunohistochemistry and quantitative RT-PCR. RESULTS Pax4 but not Pax4R129W protected animals against streptozotocin-induced hyperglycemia and isolated islets from cytokine-mediated β-cell apoptosis. Cytochrome C release was abrogated in Pax4 islets treated with cytokines. Interleukin-1β transcript levels were suppressed in Pax4 islets, whereas they were increased along with NOS2 in Pax4R129W islets. Bcl-2, Cdk4, and c-myc expression levels were increased in Pax4 islets while MafA, insulin, and GLUT2 transcript levels were suppressed in both animal models. Long-term Pax4 expression promoted proliferation of a Pdx1-positive cell subpopulation while impeding insulin secretion. Suppression of Pax4 rescued this defect with a concomitant increase in pancreatic insulin content. CONCLUSIONS Pax4 protects adult islets from stress-induced apoptosis by suppressing selective nuclear factor-κB target genes while increasing Bcl-2 levels. Furthermore, it promotes dedifferentiation and proliferation of β-cells through MafA repression, with a concomitant increase in Cdk4 and c-myc expression. |
|---|---|
| ISSN: | 1939327X 00121797 |
| DOI: | 10.2337/db10-1102 |