AJP - Endocrinology and Metabolism, Vol 267, Issue 5 E629-E635, Copyright © 1994 by American Physiological Society
Molecular pathophysiology of glucagon-SV40 T antigen transgenic mice
D. J. Drucker
Department of Medicine, University of Toronto, Ontario, Canada.
The gene encoding proglucagon is expressed in the pancreas, intestine, and
brain. The molecular determinants of proglucagon gene expression and the
biological activities of the proglucagon-derived peptides (PGDPs) have been
examined using transgenic mice harboring a glucagon-SV40 large T antigen
(GLUTag) transgene. These experiments have delineated DNA sequences
important for intestinal-specific proglucagon gene transcription. GLUTag
mice develop neuroendocrine tumors of the pancreas and large bowel, leading
to elevated plasma levels of the PGDPs and suppression of endogenous
proglucagon gene expression. Transplantation of the large bowel tumors
subcutaneously into nude mice provides additional evidence for inhibition
of endogenous pancreatic proglucagon gene expression by one or more of the
tumor-derived PGDPs. The large bowel GLUTag tumors exhibit abnormalities in
the posttranslational processing of proglucagon. GLUTag tumors may be
passaged in vivo and in vitro and have been used to generate stable cell
lines that express the proglucagon gene at high levels. Taken together,
these studies highlight the utility of transgenic systems for the
physiological analysis of hormone action and the molecular determinants of
peptide hormone gene expression.
