An endocrine-specific element is an integral component of an exocrine-specific pancreatic enhancer.

Kruse, Fred; Rose, Scott D.; Swift, Galvin H.; Hammer, Robert E.; MacDonald, Raymond J.

doi:10.1101/gad.7.5.774

Cited by 49 publications

(72 citation statements)

References 60 publications

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“…The Cre transgene and the R26R-EYFP reporter allele were never derived from the same parent as this led to embryo-wide recombination in tissues throughout the mouse. Cre transgenes included elastase 500 -Cre, containing 500 bp of the elastase promoter that has been shown to direct acinar-specific expression (Kruse et al, 1993) and with growth hormone 3Ј untranslated sequences (Postic et al, 1999);Villin-Cre (el Marjou et al, 2004), a kind gift from Sylvie Robine; Pdx1 PB -CreERT , containing the 1 kilobase islet-specific enhancer region from the Pdx1 promoter and the hsp68 minimal promoter driving expression of Cre fused to a mutated estrogen receptor hormone-binding domain that renders Cre inactive until tamoxifen administration; and RIP-CreERT (Dor et al, 2004) containing the rat insulin promoter driving expression of a similar tamoxifen-inducible CreERT protein. For these mice, tamoxifen or corn oil vehicle alone was administered at 4-6 weeks of age, in 3 doses over a 5-day time period, 2 mg/dose via intraperitoneal injection.…”

Section: Animalsmentioning

confidence: 99%

Adult pancreatic acinar cells give rise to ducts but not endocrine cells in response to growth factor signaling

et al. 2010

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SUMMARYStudies in both humans and rodents have found that insulin + cells appear within or near ducts of the adult pancreas, particularly following damage or disease, suggesting that these insulin + cells arise de novo from ductal epithelium. We have found that insulin + cells are continuous with duct cells in the epithelium that makes up the hyperplastic ducts of both chronic pancreatitis and pancreatic cancer in humans. Therefore, we tested the hypothesis that both hyperplastic ductal cells and their associated insulin + cells arise from the same cell of origin. Using a mouse model that develops insulin + cell-containing hyperplastic ducts in response to the growth factor TGF, we performed genetic lineage tracing experiments to determine which cells gave rise to both hyperplastic ductal cells and duct-associated insulin + cells. We found that hyperplastic ductal cells arose largely from acinar cells that changed their cell fate, or transdifferentiated, into ductal cells. However, insulin + cells adjacent to acinar-derived ductal cells arose from pre-existing insulin + cells, suggesting that islet endocrine cells can intercalate into hyperplastic ducts as they develop. We conclude that apparent pancreatic plasticity can result both from the ability of acinar cells to change fate and of endocrine cells to reorganize in association with duct structures.

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Section: Animalsmentioning

confidence: 99%

Adult pancreatic acinar cells give rise to ducts but not endocrine cells in response to growth factor signaling

et al. 2010

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“…15 and see below) or in transgenic animals (14). However, this promoter region can be activated by the addition of the EI enhancer (14), other enhancers (30), and artificial constructs of homomultimeric repeats of factor binding sites in both transfected cells (17) and transgenic animals (10,16,17). For the acinar 266-6 cells, the tetO-promoter construct was inactive even in the presence of cotransfected tTA.…”

Section: Resultsmentioning

confidence: 99%

“…1). By analyzing the elements individually as homomultimers or pairwise combinations of heteromultimers in transgenic mice, we have elucidated the role of each element in controlling the pancreas specificity exhibited by the complete enhancer (10,16,17). The 21-bp A element directs expression selectively to acinar cells.…”

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confidence: 99%

“…The 12-bp B element has a dual function; it directs expression itself selectively to pancreatic islet cells, whereas in acinar cells it augments the acinar specific activity of the A element approximately 20-fold. The 30-bp C element has no intrinsic ability to act on its own, but in combination with either A or B it augments their activity an order of magnitude without affecting cell specificity (10,17). Consequently, the specificity and strength of this enhancer is based on the assembly of individual elements of unique function.…”

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Integration of Tetracycline Regulation into a Cell-specific Transcriptional Enhancer

Rose

MacDonald

1997

Journal of Biological Chemistry

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The pancreas-specific transcriptional enhancer of the rat elastase I gene was modified by substituting, in turn, each of its three individual constitutive elements with the tetO element, which confers regulation by exogenous tetracycline in the presence of the hybrid tetO binding transactivator (tTA). Whereas the unmodified enhancer was active in transfected acinar tumor cells, substitution of individual elements with the tet-responsive element abolished activity. The modified enhancers were reactivated in the presence of the tTA and, upon addition of tetracycline, were silenced. Thus, substitution of individual enhancer elements renders the enhancer responsive to regulation by tetracycline. Moreover, the tTA-activated levels were 2-8-fold greater than the unmodified enhancer. The acinar cell specificity of the unmodified enhancer was retained; none of the tetOsubstituted enhancers were activated by tTA in a variety of nonacinar cell lines. These results show that a foreign and artificial transcriptional activator, tTA, can be incorporated into an enhancer to create a novel, efficient, and regulatable transcriptional control region whose cell specificity is retained.Mammalian transcriptional enhancers and promoters are composed of multiple functional elements of distinct function that contribute to overall transcriptional specificity and strength. In some instances the collection of elements and their bound factors act highly cooperatively; alteration of individual elements or their spacing can dramatically affect the overall activity of an enhancer (1, 2). A precise arrangement of the elements is necessary for the cooperative assembly of DNA binding transcription factors in an ordered nucleoprotein complex required for transcriptional activity. Interactions between bound transcription factors appear crucial as is the presence of DNA-binding proteins whose primary role is to bend DNA to facilitate those interactions (3, 4). The cooperative interaction of transcription factors within this class of enhancer creates a transcriptional activity different than the simple sum of the activities of its individual elements (2, 4). Other enhancers appear to have much more flexible organizational requirements; individual elements play only incremental roles (5, 6) and spacing requirements are much less stringent (7,8). When examined, the separate activities of these enhancers are evident in the individual elements (7-10).One approach to testing the organizational requirements of an enhancer is to examine the activity of each of its elements independently (e.g. Refs. 9 and 11-13). We have used this approach to dissect the functional elements of the transcriptional enhancer of the pancreatic elastase I (EI) 1 gene. The EI enhancer (14) comprises only three mutation-sensitive elements, termed A, B, and C (15, 16) (Fig. 1). By analyzing the elements individually as homomultimers or pairwise combinations of heteromultimers in transgenic mice, we have elucidated the role of each element in controlling the pancreas specificity exh...

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“…The transgene was created by insertion of a 530-bp rat elastase I promoter (13) into the pcDNA3.1(Ϫ) vector at the HindIII/BamHI site followed by insertion of a 1.9-kb rabbit hemoglobin intron and SV40 polyA tail into the BamHI/XhoI site (9,17). Then a full-length mouse Reg2 cDNA was inserted into the EcoRI site in the rabbit hemoglobin sequence (29).…”

Section: Methodsmentioning

confidence: 99%

Pancreatic Acinar-Specific Overexpression of Reg2 Gene Offered No Protection Against Either Experimental Diabetes or Pancreatitis in Mice.

Li¹,

Wang²

2010

The Endocrine Society's 92nd Annual Meeting, June 19–22, 2010 - San Diego

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Reg proteins are normally expressed in pancreatic acinar cells, and the level of several of these proteins was significantly induced upon damage to the endocrine or exocrine pancreas. It has been established that Reg1 and pancreatic islet neogenesis-associated protein [INGAP, Reg3␦] promote the growth or regeneration of the endocrine islet cells. Recent reports suggest that Reg2 is an autoantigen normally expressed in islet ␤-cells. Reg2 overexpression in vitro offered protection to insulinoma cells. Overexpressed Reg3␣ increased cyclin D1 and CDK4 levels and the rate of proliferation in insulinoma cells. Acinar-specific overexpression of INGAP increased ␤-cell mass and protected the animals from streptozotocin-induced diabetes. Moreover, Reg2 gene expression was induced during pancreatitis. We hypothesized that Reg2 is a secreted protein that promotes the growth, survival, and/or regeneration of pancreatic endocrine and exocrine cells. To test its effectiveness, we used elastase-1 promoter (Ela-Reg2) to develop an acinar cell-specific overexpression of the Reg2 gene. Western blot analysis, real-time PCR, and immunohistochemistry revealed barely detectable levels of endogenous Reg2 in the pancreas of normal wild-type mice and increased Reg2 levels in the pancreas of Ela-Reg2 mice that were similar to or higher than Reg2 levels induced in experimental diabetes or pancreatitis. Compared with wild-type littermates, growth, blood glucose and insulin levels, and glucose tolerance were normal in Ela-Reg2 mice; pancreatic histology revealed no change in endocrine or exocrine tissues. Acinar-specific overexpression of the Reg2 gene offered no protection against streptozotocin-induced ␤-cell damage and diabetes, in hyperglycemia and weight loss, and no advantage in restoring glucose homeostasis and islet function within 3 mo. Furthermore, serum amylase level and pancreatic histochemistry showed that Reg2 overexpression did not protect acinar cells against caerulein-induced acute pancreatitis. In contrast to INGAP or Reg3␤, exocrine overexpression of Reg2 offered no protection to the endocrine or exocrine pancreas, indicating clear subtype specificities of the Reg family of proteins.caerulein; immunohistochemistry; pancreatic islets; streptozotocin; transgenic mice REG PROTEINS CONSTITUTE a conserved family of seven members (Reg1, Reg2, Reg3␣, Reg3␤, Reg3␦, Reg3␥, and Reg4) in rodents; their production in the pancreas (including the islets of Langerhans) was induced upon endocrine ␤-cell or exocrine acinar cell damage (2,11,14,15). While some of these proteins [Reg1 and islet neogenesis-associated protein (INGAP or Reg3␦)] have been implicated in promoting ␤-cell replication and/or neogenesis in in vivo studies in transgenic and knockout mice (24 -26, 32), the roles of the other five proteins have not been well characterized. A unique seven-amino acid insertion (QVAEEDE) near its NH 2 terminus distinguishes Reg2 (found only in mice and hamsters) from other Reg proteins (4, 29). Results from a recent dual-labeled immunohi...

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An endocrine-specific element is an integral component of an exocrine-specific pancreatic enhancer.

Cited by 49 publications

References 60 publications

Adult pancreatic acinar cells give rise to ducts but not endocrine cells in response to growth factor signaling

Adult pancreatic acinar cells give rise to ducts but not endocrine cells in response to growth factor signaling

Integration of Tetracycline Regulation into a Cell-specific Transcriptional Enhancer

Pancreatic Acinar-Specific Overexpression of Reg2 Gene Offered No Protection Against Either Experimental Diabetes or Pancreatitis in Mice.

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