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doi:10.22028/D291-44140
Titel: | Ternary complex factor regulates pancreatic islet size and blood glucose homeostasis in transgenic mice |
VerfasserIn: | Lesch, Andrea Backes, Tobias M. Langfermann, Daniel S. Rössler, Oliver G. Laschke, Matthias W. Thiel, Gerald |
Sprache: | Englisch |
Titel: | Pharmacological Research |
Bandnummer: | 159 |
Verlag/Plattform: | Elsevier |
Erscheinungsjahr: | 2020 |
Freie Schlagwörter: | Islet size Glucose tolerance Elk-1 morphometry caspase-3 |
DDC-Sachgruppe: | 610 Medizin, Gesundheit |
Dokumenttyp: | Journalartikel / Zeitschriftenartikel |
Abstract: | A hallmark of diabetes mellitus is the inability of pancreatic β-cells to secrete sufficient amounts of insulin for maintaining normoglycemia. The formation of smaller islets may underlie the development of a diabetic phenotype, as a decreased β-cell mass will produce an insufficient amount of insulin. For a pharmacological intervention it is crucial to identify the proteins determining β-cell mass. Here, we identified the ternary complex factor (TCF) Elk-1 as a regulator of the size of pancreatic islets. Elk-1 mediates, together with a dimer of the serum-response factor (SRF), serum response element-regulated gene transcription. Elk-1 is activated in glucosetreated pancreatic β-cells but the biological functions of this protein in β-cells are so far unknown. Elk-1 and homologous TCF proteins are expressed in islets and insulinoma cells. Gene targeting experiments revealed that the TCF proteins show redundant activities. To solve the problem of functional redundancy of these homologous proteins, we generated conditional transgenic mice expressing a dominant-negative mutant of Elk-1 in pancreatic β-cells. The mutant competes with the wild-type TCFs for DNA and SRF-binding. Expression of the Elk-1 mutant in pancreatic β-cells resulted in the generation of significantly smaller islets and increased caspase-3 activity, indicating that apoptosis was responsible for the reduction of the pancreatic islet size. Glucose tolerance tests revealed that transgenic mice expressing the dominant-negative mutant of Elk-1 in pancreatic β-cells displayed impaired glucose tolerance. Thus, we show here for the first time that TCF controls important functions of pancreatic β-cells in vivo. Elk-1 may be considered as a new therapeutic target for the treatment of diabetes. |
DOI der Erstveröffentlichung: | 10.1016/j.phrs.2020.104983 |
URL der Erstveröffentlichung: | https://doi.org/10.1016/j.phrs.2020.104983 |
Link zu diesem Datensatz: | urn:nbn:de:bsz:291--ds-441404 hdl:20.500.11880/39473 http://dx.doi.org/10.22028/D291-44140 |
ISSN: | 1043-6618 |
Datum des Eintrags: | 24-Jan-2025 |
Bezeichnung des in Beziehung stehenden Objekts: | Supplementary data |
In Beziehung stehendes Objekt: | https://ars.els-cdn.com/content/image/1-s2.0-S1043661820312913-mmc1.pdf |
Fakultät: | M - Medizinische Fakultät |
Fachrichtung: | M - Chirurgie M - Medizinische Biochemie und Molekularbiologie |
Professur: | M - Prof. Dr. Michael D. Menger M - Prof. Dr. Gerald Thiel |
Sammlung: | SciDok - Der Wissenschaftsserver der Universität des Saarlandes |
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