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Glucose-Induced Expression of the Cyclin-Dependent Protein Kinase 5 Activator p35 Involved in Alzheimer’s Disease Regulates Insulin Gene Transcription in Pancreatic ß-Cells

Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Howard Hughes Medical Institute and Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Joel F. Habener, M.D., Laboratory of Molecular Endocrinology, Massachusetts General Hospital, 55 Fruit Street, Wellman 306, Boston, Massachusetts 02114. E-mail: jhabener{at}partners.org.

The deposition of amyloid within the insulin-producing islets of Langerhans in the pancreas is a common pathological finding in patients with type 2 diabetes. Its relationship with age and the progression of the disease resembles the pathological deposition of ß-amyloid in the brains of Alzheimer’s patients. Endocrine cells of pancreatic islets and cells of neuronal lineages express a shared subset of specialized genes. The hyperactivity of the cyclin-dependent protein kinase CDK5, involved in the development and differentiation of the nervous system, is associated with Alzheimer’s disease. Overactivity of CDK5 occurs by proteolytic cleavage and cellular mislocalization of its activator, p35. These alterations in p35/CDK5 signaling pathway may mediate, at least in part, the functional abnormalities characteristic of Alzheimer’s disease. In this study we report that both the p35 and CDK5 genes are expressed in insulin-producing ß-cells of the pancreas. We detect in ß-cells the formation of an active p35/CDK5 complex with specific kinase activity. Notably, elevations of the extracellular concentration of glucose result in increases in p35 mRNA and protein levels that parallel elevations of p35/CDK5 activity. Functional studies show that p35 stimulates the activity of the insulin promoter and that the stimulation requires CDK5 because stimulation is blocked by roscovitine, an inhibitor of CDK5 activity, a dominant negative form of CDK5, and small interfering RNAs against p35. Our findings indicate that the expression of p35 and CDK5 in insulin-producing ß-cells ensembles a new signaling pathway, the activity of which is controlled by glucose, and its functional role may comprise the regulation of various biological processes in ß-cells, such as is the case for expression of the insulin gene.

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