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.