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Transcription Factors in Islet Development and Physiology: Role of PDX-1 in Beta-Cell Function
DANIELLE MELLOUL
Department of Endocrinology and Metabolism, The Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Address for correspondence: Dr. Danielle Melloul, Department of Endocrinology and Metabolism, The Hadassah-Hebrew University Medical Center, PO Box 12000, 91120 Jerusalem, Israel. Voice: (972)-2-677 83 98; fax: (972)-2-6437 940. danielle{at}md.huji.ac.il
Ann. N.Y. Acad. Sci. 1014: 28-37 (2004).
Differentiation of early foregut endoderm into pancreatic endocrine and exocrine cells depends on a cascade of gene activation events controlled by various transcription factors. The first molecular marker identified that specifies the early pancreatic epithelium is the homeodomain-containing transcription factor PDX-1. Its absence in mice and humans during development leads to agenesis of the pancreas. Later, it becomes restricted primarily to ß cells where it regulates the expression of ß cell-specific genes, and, most importantly, mediates the glucose effect on insulin gene transcription. Although exposure of ß cells to high glucose concentrations for relatively short periods stimulates insulin gene expression, chronic exposure has adverse effects on many ß-cell functions, including insulin gene transcription. These events appear to correlate with pdx-1 gene expression and its ability to bind the insulin gene. We consider that loss of PDX-1 function or altered pdx-1 gene expression due to mutations or functional impairment of transcription factors controlling its expression can lead to diabetes.
Key Words: pancreas • islet • beta cell • insulin • transcription factors • PDX-1 • diabetes
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