Overexpression of heparin-binding EGF-like growth factor in mouse pancreas results in fibrosis and epithelial metaplasia

Means, Anna L.; Ray, Kevin C.; Singh, Amar; Washington, M. Kay; Whitehead, Robert H.; Harris, Raymond C.; Wright, Christopher V.E.; Coffey, Robert J.; Leach, Steven D.

doi:10.1053/gast.2003.50150

Cited by 93 publications

(75 citation statements)

References 70 publications

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“…Also in agreement with our previous results is the lack of pathological alterations in PIP-hBTC transgenic mice. This is in contrast to the multiple pathological effects including islet disaggregation, fibrosis, and even ductal metaplasia observed in transgenic mice with -cell-specific overexpression of the EGFR ligands EGF (Krakowski et al 1999) and heparin-binding EGF (Means et al 2003). This observation indicates that BTC has unique actions on pancreatic islets as compared to other EGFR ligands.…”

Section: Discussionmentioning

confidence: 81%

Specific transgene expression in mouse pancreatic β-cells under the control of the porcine insulin promoter

Grzech¹,

Dahlhoff²,

Herbach³

et al. 2010

Molecular and Cellular Endocrinology

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The availability of regulatory sequences directing tissue-specific expression of transgenes in genetically modified mice and large animals is a prerequisite for the development of adequate models for human diseases. The rat insulin 2 gene (Ins2) promoter, widely used to achieve transgene expression in pancreatic -cells of mice, also directs expression to extrapancreatic tissues and performs poorly in isolated pancreatic islets of human, mouse, and pig. To evaluate whether the full 5' untranslated region (UTR) of the porcine insulin gene (INS) confers robust and specific expression in -cells we generated an expression cassette containing 1500 bp of the porcine INS 5' UTR and the 3' UTR of the bovine growth hormone gene (GH). The cassette was designed to allow easy exchange of the sequences to be expressed and easy removal of the vector backbone from the expression cassette. To evaluate the properties of the cassette, we initially cloned a cDNA encoding human betacellulin, a growth factor known to affect structural and functional parameters of -cells. After confirming the functionality and specificity of the construct in vitro, transgenic mouse lines were generated by pronuclear DNA microinjection. Using RT-PCR, immunohistochemistry and immunofluorescence, we show that transgenic mice expressed human betacellulin exclusively in -cells. Confirming the proposed insulinotropic effect of betacellulin, transgenic mice showed improved glucose tolerance. We conclude that the newly designed expression cassette containing 1.500 bp of the porcine insulin promoter 5' UTR confers robust and specific transgene expression to -cells in vitro and in transgenic mice.

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Section: Discussionmentioning

confidence: 81%

Specific transgene expression in mouse pancreatic β-cells under the control of the porcine insulin promoter

Grzech¹,

Dahlhoff²,

Herbach³

et al. 2010

Molecular and Cellular Endocrinology

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“…It has been reported that duct-like cells or tubular complexes appear in both pancreatitis and pancreatic neoplasia in humans and rodent models (Parsa et al 1985;Bockman 1997;Wagner et al 1998;Song et al 1999;Means et al 2003). Song et al (1999) have observed the up-regulation of PDX-1 expression in the metaplastic ductal epithelium of transgenic mice overexpressing transforming growth factor-␣ (TGF-␣).…”

Section: Pdx-1 Causes Acinoductal Metaplasia Genes and Development 1437mentioning

confidence: 99%

Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation

Miyatsuka¹,

Kaneto²,

Shiraiwa³

et al. 2006

Genes Dev.

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147

136

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The transcription factor pancreatic and duodenal homeobox factor 1 (PDX-1) is expressed in pancreatic progenitor cells. In exocrine pancreas, PDX-1 is down-regulated during late development, while re-up-regulation of PDX-1 has been reported in pancreatic cancer and pancreatitis. To determine whether sustained expression of PDX-1 could affect pancreas development, PDX-1 was constitutively expressed in all pancreatic lineages by transgenic approaches. The transgenic pancreas was markedly small with the replacement of acinar cells by duct-like structures, accompanied by activated Stat3. Genetic ablation of Stat3 in the transgenic pancreas profoundly suppressed the metaplastic phenotype. These results provide a mechanism of pancreatic metaplasia by which persistent PDX-1 expression cell-autonomously induces acinar-to-ductal transition through Stat3 activation.Supplemental material is available at http://www.genesdev.org.

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“…(42,43) Overexpression of HB-EGF in the mouse pancreas leads to fibrosis and epithelial metaplasia. (44) Helicobacter pylori, which has a major etiological role in human gastric carcinogenesis, induces the activation of EGFR signaling mediated by the cleavage of proHB-EGF to promote enhanced gastric epithelial proliferation and gastric neoplasia. (45)(46)(47) Furthermore, in vitro experiments have shown that addition of an anti-HB-EGF blocking antibody to human glioblastoma cells reduces proliferation by 30 -40% compared with the addition of normal goat IgG.…”

Section: Cell Proliferationmentioning

confidence: 99%

Heparin‐binding epidermal growth factor‐like growth factor as a novel targeting molecule for cancer therapy

et al. 2006

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Overexpression of heparin-binding EGF-like growth factor in mouse pancreas results in fibrosis and epithelial metaplasia

Cited by 93 publications

References 70 publications

Specific transgene expression in mouse pancreatic β-cells under the control of the porcine insulin promoter

Specific transgene expression in mouse pancreatic β-cells under the control of the porcine insulin promoter

Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation

Heparin‐binding epidermal growth factor‐like growth factor as a novel targeting molecule for cancer therapy

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