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MafA Regulates Expression of Genes Important to Islet ß-Cell Function

Department of Internal Medicine and Therapeutics (T.Ma., H.K., T.Mi., D.K., M.M., M.H., Y.Y.), Osaka University Graduate School of Medicine, Suita 565-0871, Japan; Department of Molecular Physiology and Biophysics (R.S., E.H.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and Institute for Molecular and Cellular Regulation (I.K.), Gunma University, Maebashi 371-8512, Japan

Address all correspondence and requests for reprints to: Taka-aki Matsuoka, Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871 Japan. E-mail: takaaki{at}medone.med.osaka-u.ac.jp.

Insulin transcription factor MafA is unique in being exclusively expressed at the secondary and principal phase of insulin-expressing cell production during pancreas organogenesis and is the only transcriptional activator present exclusively in islet ß-cells. Here we show that ectopic expression of MafA is sufficient to induce a small amount of endogenous insulin expression in a variety of non-ß-cell lines. Insulin mRNA and protein expression was induced to a much higher level when MafA was provided with two other key insulin activators, pancreatic and duodenal homeobox (PDX-1) and BETA2. Potentiation by PDX-1 and BETA2 was entirely dependent upon MafA, and MafA binding to the insulin enhancer region was increased by PDX-1 and BETA2. Treatment with activin A and hepatocyte growth factor induced even larger amounts of insulin in AR42J pancreatic acinar cells, compared with other non-ß endodermal cells. The combination of PDX-1, BETA2, and MafA also induced the expression of other important regulators of islet ß-cell activity. These results support a critical role of MafA in islet ß-cell function.