Glucagon gene 5'-flanking sequences direct expression of simian virus 40 large T antigen to the intestine, producing carcinoma of the large bowel in transgenic mice
Glucagon and the glucagon-like peptides play important roles in the regulation of glucose homeostasis. Previous studies have demonstrated that approximately 1300 base pairs of rat glucagon gene 5'-flanking sequences direct transgene expression to the pancreas and brain, but not to the intestine...
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Veröffentlicht in: | The Journal of biological chemistry 1992-05, Vol.267 (15), p.10705-10708 |
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Zusammenfassung: | Glucagon and the glucagon-like peptides play important roles in the regulation of glucose homeostasis. Previous studies have
demonstrated that approximately 1300 base pairs of rat glucagon gene 5'-flanking sequences direct transgene expression to
the pancreas and brain, but not to the intestine, of transgenic mice. These observations suggested that different tissue-specific
enhancer elements mediate activation of glucagon gene transcription in the pancreas and intestine. We have now generated mice
that express SV40 large T antigen under the control of approximately 2000 base pairs of glucagon gene 5'-flanking sequences.
Transgene expression was observed in the brain and pancreas in association with the development of pancreatic endocrine tumors.
In contrast to the mice described previously, we also detected transgene expression throughout the gastrointestinal tract
in endocrine cells of the stomach and small and large intestine. Focal areas of enteroendocrine cell hyperplasia in the large
bowel invariably progressed to invasive and metastasizing plurihormonal endocrine carcinoma, which was clinically and pathologically
evident by 4 weeks of age. In contrast, transgene expression in the small bowel and stomach was not associated with progression
to either hyperplasia or carcinoma. The results of these studies provide functional evidence for the existence of an upstream
cis-acting regulatory domain that directs glucagon gene transcription to the endocrine cells of the intestine in transgenic
mice. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1016/S0021-9258(19)50075-8 |