| Overexpression of p35 in Min6 pancreatic beta cells induces a stressed neuron-like apoptosis. | |
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MedLine Citation:
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PMID: 20926102 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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Cdk5 activity has been implicated in brain development and the regulation of many neuronal processes. Recently, the expression of p35 and Cdk5 activity has been reported in pancreatic beta cells. Decreased Cdk5 activity enhanced glucose-stimulated insulin secretion. This suggests that Cdk5 may play an important role in the regulation of insulin secretion. To further understand how Cdk5 regulates insulin secretion in glucose-stimulated pancreatic β cells, we first confirmed the presence of a low level of p35 in pancreatic Min6 cells. Next, in a time-course experiment in high glucose (25 mM) we showed that endogenous p35 increased gradually accompanied by a 3-fold increase in Cdk5 activity by 16 h. Insulin secretion, however, doubled after 2 h followed by progressive downregulation, negatively correlated with Cdk5 activity. On the other hand, overexpression of p35 in these cells resulted in more than a three-fold increase in Cdk5 activity within 2 h coupled to a 50% reduction in insulin secretion in both high and low (3 mM) glucose. Most significantly, cells overexpressing p35, treated with high glucose for 4 h, showed induction of p25, the p35-derived truncated fragment which hyperactivates Cdk5 in neurons. As a result, insulin secretion was inhibited and cells became apoptotic. Roscovitine or co-infection of dominant negative Cdk5 (dnCdk5) with p35 increased insulin secretion and inhibited apoptosis. These results suggest that the model for deregulation and hyperactivation of Cdk5 in neurodegeneration may apply to the pathology seen in type 2 diabetes (T2DM). It is consistent with the view that Alzheimer's disease and T2DM are linked metabolically and pathologically by Cdk5 in a number of ways. |
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Authors:
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Ya-Li Zheng; Ya-Fang Hu; Aiping Zhang; Wei Wang; Bo Li; Niranjana Amin; Philip Grant; Harish C Pant |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Intramural |
Journal Detail:
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Title: Journal of the neurological sciences Volume: 299 ISSN: 1878-5883 ISO Abbreviation: J. Neurol. Sci. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-11-29 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0375403 Medline TA: J Neurol Sci Country: Netherlands |
Other Details:
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Languages: eng Pagination: 101-7 Citation Subset: IM |
Copyright Information:
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Copyright © 2010. Published by Elsevier B.V. |
Affiliation:
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Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health, USA. yalinew@yahoo.com |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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