Proglucagon processing similar to normal islets in pancreatic alpha-like cell line derived from transgenic mouse tumor

Abstract

A pancreatic alpha-like cell line has been established from a glucagonoma arising in transgenic mice expressing a hybrid gene consisting of the rat glucagon-promoter sequence fused to the sequence encoding the SV40 T-antigen oncoprotein. The alpha-tumor cell 1 (alpha TC1) line maintained many characteristics of differentiated alpha-cells for greater than 40 passages in culture and expressed levels of glucagon mRNA 5- to 10-fold higher than those reported previously in rat and hamster islet cell lines. By radioimmunoassay, the cells synthesized considerable amounts of glucagon, glucagonlike peptide I (GLP-I), the major proglucagon fragment, and small amounts of unprocessed proglucagon but no free GLP-II. This distribution of peptides is similar to that found in extracts of rodent pancreases and is distinct from that seen with other islet cell lines, which process proglucagon in patterns more characteristic of intestinal cells. The GLP-I peptide in the alpha TC1 cell line was in the form of GLP-I-(1-37), which is inactive as a stimulator of insulin secretion, and not GLP-I-7-37) or -(7-36)-amide peptides, both of which are potent insulin secretagogues. The alpha TC1 cell line produced glucagon-related peptides in a relatively uniform pattern by immunocytochemistry, and electron microscopy revealed typical alpha-type (glucagon) secretory granules. Although the cell line was derived from an islet tumor producing only glucagon, the alpha TC1 cell line also produced insulin in addition to the glucagon peptides.(ABSTRACT TRUNCATED AT 250 WORDS)