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Evidence for a Role of the Ubiquitin-Proteasome Pathway in Pancreatic Islets

From the Section on Islet Transplantation and Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts

Address correspondence and reprint requests to María D. López-Avalos, PhD, Dpt. Biología Celular, Genética y Fisiología, Facultad de Ciencias, Universidad de Málaga, Campus de Teatinos, Málaga 29071, Spain. E-mail: lopezavalos{at}uma.es

Abbreviations: E6-AP, E6-associated protein; NF-B, nuclear factor-B; PKC, protein kinase C; PGP9.5, protein gene product 9.5; TRCP, transducin repeat–containing protein

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 ß-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 ß-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.

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