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Aberrant Regulation of Human Intestinal Proglucagon Gene Expression in the NCI-H716 Cell Line

Departments of Medicine (D.J.D.), Laboratory Medicine and Pathobiology (D.M.I., D.J.D.), Banting and Best Diabetes Centre (X.C., G.F., C.C., D.M.I., D.J.D.), Toronto General Hospital, University of Toronto, Toronto, Canada M5G 2C4

Address all correspondence and requests for reprints to: Dr. D. Drucker, Banting and Best Diabetes Centre, Toronto General Hospital, 200 Elizabeth Street MBRW4R-402, Toronto, Ontario, Canada M5G 2C4. E-mail: d.drucker{at}utoronto.ca.

Despite interest in understanding glucagon-like peptide-1 (GLP-1) production, the factors important for GLP-1 biosynthesis remain poorly understood. We examined control of human proglucagon gene expression in NCI-H716 cells, a cell line that secretes GLP-1 in a regulated manner. Insulin, phorbol myristate acetate, or forskolin, known regulators of rodent proglucagon gene expression, had no effect, whereas sodium butyrate decreased levels of NCI-H716 proglucagon mRNA transcripts. The inhibitory effect of sodium butyrate was mimicked by trichostatin A but was not detected with sodium acetate or isobutyrate. The actions of butyrate were not diminished by the ERK1/2 inhibitor PD98059, p38 inhibitor SB203580, or soluble guanylate cyclase inhibitor LY83583 or following treatment of cells with KT5823, a selective inhibitor of cGMP-dependent protein kinase. NCI-H716 cells expressed multiple proglucagon gene transcription factors including isl-1, pax-6, pax-2, cdx-2/3, pax-4, hepatocyte nuclear factor (HNF)-3, HNF-3ß, HNF-3, and Nkx2.2. Nevertheless, the butyrate-dependent inhibition of proglucagon gene expression was not associated with coordinate changes in transcription factor expression and both the human and rat transfected proglucagon promoters were transcriptionally inactive in NCI-H716 cells. Hence, NCI-H716 cells may not be a physiologically optimal model for studies of human enteroendocrine proglucagon gene transcription.

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