Identification of a transcriptional enhancer important for enteroendocrine and pancreatic islet cell-specific expression of the secretin gene.

Wheeler, M B; Nishitani, J; Buchan, A M; Kopin, A S; Chey, William Y.; Chang, Ta‐Min; Leiter, Andrew B.

doi:10.1128/mcb.12.8.3531

Cited by 53 publications

(48 citation statements)

References 28 publications

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“…Other factors also regulate islet growth both in fetal development and postnatally. Like gastrin, secretin and thyroid-releasing hormone are transiently expressed in the fetal islets and may also influence pancreatic development (31,32), although there is no direct evidence for such a role. IGF-1 is also expressed in fetal islets and has been reported to stimulate replication of isolated islets in culture (33).…”

Section: Discussionmentioning

confidence: 99%

Pancreatic gastrin stimulates islet differentiation of transforming growth factor alpha-induced ductular precursor cells.

Wang¹,

Bonner-Weir²,

Oates³

et al. 1993

J. Clin. Invest.

264

190

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Gastrin is transiently expressed in fetal islets during a critical period of their development from protodifferentiated islet precursors in fetal pancreatic ducts. To examine the possible role of gastrin as an islet cell growth factor, postnatal islet growth was studied in transgenic mice which overexpress gastrin and TGFa in their pancreas. Overexpression of a TGFa transgene causes metaplastic ductules containing numerous insulin expressing cells that resemble protodifferentiated precursors of the fetal pancreas. However, islet mass of the TGFa transgenic mice was not increased. Pancreatic overexpression of gastrin from a chimeric insulin/gastrin transgene transcribed from the insulin promoter markedly decreased the TGFa-stimulated increase in pancreatic duct mass. Furthermore, pancreatic coexpression of both gastrin and TGFa significantly increased islet mass in mice expressing both transgenes. These findings indicate that TGFa and gastrin can act synergistically to stimulate islet growth, although neither peptide alone is sufficient. Islet growth may possibly be stimulated through gastrin promoting the differentiation of insulin-positive cells in the TGFa-induced metaplastic ducts. This transgenic study suggests that islet neogenesis can be reactivated in the ductular epithelium of the adult pancreas by local expression of two growth factors, gastrin and TGFa. (J. Clin. Invest. 1993. 92:1349-1356

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Section: Discussionmentioning

confidence: 99%

Pancreatic gastrin stimulates islet differentiation of transforming growth factor alpha-induced ductular precursor cells.

Wang¹,

Bonner-Weir²,

Oates³

et al. 1993

J. Clin. Invest.

264

190

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“…The secretin-luciferase reporter gene constructions for transient expression assays consisted of sequences from Ϫ209 to ϩ32 of the rat secretin gene (38) with or without mutations cloned upstream of the structural gene encoding firefly luciferase. We generated a series of transversion mutants (A7C and G7T) in the secretin promoter by site-directed mutagenesis (12) and confirmed the presence of the desired mutations by DNA sequencing.…”

Section: Methodsmentioning

confidence: 99%

“…The enhancer was necessary and sufficient for high levels of reporter gene expression in secretin-expressing cell lines but had no activity in cell lines that did not express their endogenous secretin gene (38). Examination of a series of 5Ј-and 3Ј-deletion mutants within the enhancer revealed a stepwise loss of activity with deletions of increasing size, suggesting that the enhancer was comprised of multiple regulatory elements.…”

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confidence: 99%

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Novel Transcriptional Potentiation of BETA2/NeuroD on the Secretin Gene Promoter by the DNA-Binding Protein Finb/RREB-1

Ray

Nishitani

Petry

et al. 2003

Molecular and Cellular Biology

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The basic helix-loop-helix protein BETA2/NeuroD activates transcription of the secretin gene and is essential for terminal differentiation of secretin-producing enteroendocrine cells. However, in heterodimeric complexes with its partner basic helix-loop-helix proteins, BETA2 does not appear to be a strong activator of transcription by itself. Mutational analysis of a proximal enhancer in the secretin gene identified several cis-acting elements in addition to the E-box binding site for BETA2. We identified by expression cloning the zinc finger protein RREB-1, also known to exist as a longer form, Finb, as the protein binding to one of the mutationally sensitive elements. Finb/RREB-1 lacks an intrinsic activation domain and by itself did not activate secretin gene transcription. Here we show that Finb/RREB-1 can associate with BETA2 to enhance its transcription-activating function. Both DNA binding and physical interaction of Finb/RREB-1 with BETA2 are required to potentiate transcription. Thus, Finb/RREB-1 does not function as a classical activator of transcription that recruits an activation domain to a DNA-protein complex. Finb/RREB-1 may be distinguished from coactivators, which increase transcription without sequence-specific DNA binding. We suggest that Finb/RREB-1 should be considered a potentiator of transcription, representing a distinct category of transcription-regulating proteins.The expression of secretin, a peptide hormone, is restricted to S-type enteroendocrine cells present primarily in the small intestine and in the colon. The gene is also transiently expressed in normal ␤ cells of developing pancreatic islets as well as in several pancreatic and intestinal endocrine cell lines (38). It was previously shown that 1.6 kb of 5Ј-flanking sequence of the secretin gene conferred tissue-specific, developmentally regulated expression of a reporter gene in transgenic mice (19).Analysis of the secretin gene promoter by transient expression assays identified an enhancer between Ϫ174 and Ϫ53 bp 5Ј of the transcription initiation site. The enhancer was necessary and sufficient for high levels of reporter gene expression in secretin-expressing cell lines but had no activity in cell lines that did not express their endogenous secretin gene (38). Examination of a series of 5Ј-and 3Ј-deletion mutants within the enhancer revealed a stepwise loss of activity with deletions of increasing size, suggesting that the enhancer was comprised of multiple regulatory elements.A consensus E box sequence at Ϫ130 was required for full promoter activity. BETA2/NeuroD, a basic helix-loop-helix (bHLH) transcription factor that was originally identified as a transactivator of the insulin gene (25) and as a neurogenic factor in Xenopus embryos (15), was subsequently shown to bind the secretin gene E-box as a heterodimer with the ubiquitously expressed bHLH protein E12 or E47 (22).BETA2 is expressed in a very limited number of tissues, including neurons, the anterior pituitary, pancreatic islets, and enteroendocrine cells. The insuli...

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“…At present there are no known functions for the N or C-terminal peptides. Secretin gene expression is regulated by a 5' flanking sequence (115). The entire 27 amino acid sequence is required for maximal potency but the 5-27 amino acid Cterminal fragment has partial activity (71).…”

Section: Generalmentioning

confidence: 99%

Secretin

The Pancreapedia: Exocrine Pancreas Knowledge Base

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Secretin is one of the "classical" gastrointestinal hormones and in fact was the first peptide hormone identified. The mature hormone is a 27 amino acid peptide produced and secreted by a specific type of enteroendocrine cell, the S cell which is of the open type with its apical surface exposed to luminal content. Secretin is packaged into granules and released across the basolateral membrane into the blood in response to acid in the duodenum when the pH falls below 4.5; it is also released in response to fatty acids but without a response to glucose or amino acids. Basal and stimulated concentrations are low normally in the 1-10 pM range. The principal action of secretin is to stimulate bicarbonate secretion by pancreatic and biliary ducts and duodenal Brunner's glands into the lumen such that acid in the duodenum will be neutralized. Secretin also acts to potentiate CCK action on acinar cells, to inhibit gastric acid secretion and to inhibit gastric emptying. Secretin also has actions in the brain. At the cellular level the action of secretin is primarily mediated by cAMP which is increased in response to activation of secretin receptors.

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Identification of a transcriptional enhancer important for enteroendocrine and pancreatic islet cell-specific expression of the secretin gene.

Cited by 53 publications

References 28 publications

Pancreatic gastrin stimulates islet differentiation of transforming growth factor alpha-induced ductular precursor cells.

Pancreatic gastrin stimulates islet differentiation of transforming growth factor alpha-induced ductular precursor cells.

Novel Transcriptional Potentiation of BETA2/NeuroD on the Secretin Gene Promoter by the DNA-Binding Protein Finb/RREB-1

Secretin

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