Evidence for a role of the ubiquitin-proteasome pathway in pancreatic islets.
The ubiquitin-proteasome pathway is crucial for protein turnover. Part of the pathway involves deubiquitination, which is carried out by cystein proteases known as ubiquitin COOH-terminal hydrolases. The isoform Uch-L1 was found to be present in large amounts in rat islets by immunostaining, Western blot analysis, and RT-PCR. Culturing islets in high glucose concentrations (16.7 mmol/l) for 24 h led to decreased gene expression. Exposure to chronic hyperglycemia following 90% partial pancreatectomy also led to reduced Uch-L1 expression. Expression of other members of the ubiquitin-proteasome pathway studied after culturing islets at high glucose concentrations revealed little change except for modest declines in parkin, human ubiquitin-conjugating enzyme 5 (UbcH5), and beta-TRCP (transducin repeat-containing protein). With the pancreatectomy model, expression of polyubiquitin-B and c-Cbl were increased and E6-associated protein was reduced. Further insight about the proteasome pathway was obtained with the proteasome inhibitor lactacystin, which in short-term 2-h experiments enhanced glucose-induced insulin secretion. An important role for the ubiquitin-proteasome pathways in beta-cells is suggested by the findings that changes in glucose concentration influence expression of genes in the pathway and that blockade of the proteasome degradation machinery enhances glucose-stimulated insulin secretion.
López-Avalos
María D
MD
Section on Islet Transplantation and Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA. lopezavalos@uma.es
Duvivier-Kali
Valérie F
VF
Xu
Gang
G
Bonner-Weir
Susan
S
Sharma
Arun
A
Weir
Gordon C
GC
D001483:Base Sequence; D003546:Cysteine Endopeptidases / Q000378:metabolism; D017931:DNA Primers; D007515:Islets of Langerhans / Q000201:enzymology / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025801:Ubiquitin / Q000502:physiology*; D043222:Ubiquitin Thiolesterase / Q000235:genetics
D017931:DNA Primers; C482860:UCHL1 protein, human; D025801:Ubiquitin; D043222:Ubiquitin Thiolesterase; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex