This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Demeterco, C. Articles by Levine, F. Search for Related Content PubMed PubMed Citation Articles by Demeterco, C. Articles by Levine, F.

c-Myc Controls Proliferation Versus Differentiation in Human Pancreatic Endocrine Cells

Cancer Center, University of California (C.D., P.I.-A., B.T., F.L.), San Diego, California 92037; and Ambion, Inc. (L.P.F., R.A.J.), Austin, Texas 78744

Address all correspondence and requests for reprints to: Dr. Fred Levine, University of California Cancer Center, 10901 North Torrey Pines Road, Building Seven, First Floor, La Jolla, California 92037. E-mail: . flevine{at}ucsd.edu

Abstract

Using immortalized human pancreatic endocrine cell lines, we have shown previously that differentiation into hormone-expressing cells requires cell-cell contact acting in synergy with the homeodomain transcription factor pancreatic duodenal homeobox-1 (PDX-1). Although differentiation is associated with a decrease in cell proliferation, the mechanisms behind this relationship are not known. Using TRM-6, a cell line, and ßlox5, a ß-cell line, we show here that cell-cell contact and subsequent endocrine differentiation lead to a down-regulation of the c-myc protooncogene. Overexpression of c-Myc obtained with an inducible c-Myc-estrogen receptor fusion protein results in an increase in cell proliferation and the ablation of hormone expression. Moreover, we show that although c-Myc is expressed in a subset of cells from the human fetal and adult pancreas, it is absent in differentiated endocrine cells. The mechanism by which c-Myc interferes with hormone expression may be through effects on the homeodomain transcription factor PDX-1, as immunostaining for PDX-1 in cells with activated c-Myc revealed a redistribution of PDX-1 from the nucleus to the cytoplasm. These results suggest that c-Myc plays a central role in a cell-cell contact-mediated switch mechanism by which cell division vs. differentiation in endocrine cells is determined.

This article has been cited by other articles:

				K. Matsumura, B. H.-J. Chang, M. Fujimiya, W. Chen, R. N. Kulkarni, Y. Eguchi, H. Kimura, H. Kojima, and L. Chan Aquaporin 7 Is a {beta}-Cell Protein and Regulator of Intraislet Glycerol Content and Glycerol Kinase Activity, {beta}-Cell Mass, and Insulin Production and Secretion Mol. Cell. Biol., September 1, 2007; 27(17): 6026 - 6037. [Abstract] [Full Text] [PDF]