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- Title
Molecular Mechanisms of Glucotoxicity: A Potential Role of the Ubiquitin-Proteasome Pathway in the Deleterious Effects of Hyperglycemia on CREB-Mediated Pancreatic Beta-Cell Survival.
- Authors
Costes, Safia; Broca, Christophe; Bertrand, Gyslaine; Linck, Nathalie; Bockaert, Joel; Dalle, Stephane
- Abstract
Recent reports point to the transcription factor CREB (cAMP-Response Element-Binding protein) as a novel target for strategies aimed at improving β-cell survival. Since chronic hyperglycemia induces β-cell apoptosis and knowing the importance of CREB in β-cell survival, we investigated whether prolonged exposure to elevated concentration of glucose adversely affects the functional integrity of CREB and, if so, we identified the molecular mechanisms involved. Treatment of INS-1E cells (48 h) or isolated rat islets (96 h) with high glucose (30 mM) induces a decrease (50%) in CREB protein content associated with emergence of cleaved caspase-3 and morphological features of apoptosis observed by electron microscopy. However, CREB mRNA remains unaffected as measured by real-time quantitative RT-PCR, indicating that chronic high glucose decreases CREB protein expression most probably at posttranscriptional level. Treatment of INS-1E cells with the proteasome inhibitor MG132 (150 nM) blocked CREB degradation induced by high glucose. By immunoprecipitation, we found that CREB becomes ubiquitinated upon chronic high glucose treatment, confirming that CREB has a potential ubiquitin-binding domain within its primary structure. To investigate whether a protection of CREB from the ubiquitin-mediated proteasomal degradation prevents β-cell apoptosis, an original approach was designed to specifically block CREB ubiquitination. High glucose-treated INS-1E cells were transfected with peptides mimicking the ubiquitin-binding domain of CREB coupled to an HIV-tat sequence to facilitate cell transfection. Transfection of these peptides resulted in decrease in CREB ubiquitination and degradation, and, more importantly, the emergence of cleaved caspase-3 was significantly reduced. Our study reports that prolonged exposure of β-cells to high glucose induces CREB ubiquitination and proteasomal degradation. Preventing CREB from ubiquitinmediated proteasomal degradation protects β-cells from the pro-apoptotic effects of hyperglycemia.
- Publication
Diabetes, 2007, Vol 56, pA409
- ISSN
0012-1797
- Publication type
Academic Journal