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Transcriptional profiling reveals functional links between RasGrf1 and Pttg1 in pancreatic beta cells

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Transcriptional profiling reveals functional links between RasGrf1 and Pttg1 in pancreatic beta cells

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dc.contributor.author Manyes Font, Lara
dc.contributor.author Arribas, Monica
dc.contributor.author Gomez, Carmela
dc.contributor.author Calzada, Nuria
dc.contributor.author Fernandez Medarde, Alberto
dc.contributor.author Santos, Eugenio
dc.date.accessioned 2014-12-19T10:50:23Z
dc.date.available 2014-12-19T10:50:23Z
dc.date.issued 2014
dc.identifier.citation Manyes, Lara Arribas, Monica Gomez, Carmela Calzada, Nuria Fernandez Medarde, Alberto Santos, Eugenio 2014 Transcriptional profiling reveals functional links between RasGrf1 and Pttg1 in pancreatic beta cells Bmc Genomics
dc.identifier.uri http://hdl.handle.net/10550/41080
dc.description.abstract Background: Our prior characterization of RasGrf1 deficient mice uncovered significant defects in pancreatic islet count and size as well as beta cell development and signaling function, raising question about the mechanisms linking RasGrf1 to the generation of those"pancreatic" phenotypes. Results: Here, we compared the transcriptional profile of highly purified pancreatic islets from RasGrf1 KO mice to that of WT control animals using commercial oligonucleotide microarrays. RasGrf1 elimination resulted in differential gene expression of numerous components of MAPK- and Calcium-signaling pathways,suggesting a relevant contribution of this GEF to modulation of cellular signaling in the cell lineages integrating the pancreatic islets. Whereas the overall transcriptional profile of pancreatic islets was highly specific in comparison to other organs of the same KO mice, a significant specific repression of Pttg1 was a common transcriptional alteration shared with other tissues of neuroectodermal origin. This observation,together with the remarkable pancreatic phenotypic similarities between RasGrf1 KO and Pttg1 KO mice suggested the possibility of proximal functional regulatory links between RasGrf1 and Pttg1 in pancreatic cell lineages expressing these proteins. Analysis of the mPttg1 promoter region identified specific recognition sites for numerous transcription factors which were also found to be differentially expressed in RasGrf1 KO pancreatic islets and are known to be relevant for Ras-ERK signaling as well as beta cell function. Reporter luciferase assays in BT3 insulinoma cells demonstrated the ability of RasGrf1 to modulate mPttg1 promoter activity through ERK-mediated signals. Analysis of the phenotypic interplay between RasGrf1 and Pttg1 in double knockout RasGrf1/Pttg1 mice showed that combined elimination of the two loci resulted in dramatically reduced values of islet and beta cell count and glucose homeostasis function which neared those measured in single Pttg1 KO mice and were significantly lower than those observed in individual RasGrf1 KO mice. Conclusions: The specific transcriptional profile and signaling behavior of RasgGrf1 KO pancreatic islets, together with the dominance of Pttg1 over RasGrf1 with regards to the generation of these phenotypes in mouse pancreas, suggest that RasGrf1 is an important upstream component of signal transduction pathways regulating Pttg1 expression and controlling beta cell development and physiological responses
dc.language.iso eng
dc.relation.ispartof Bmc Genomics, 2014
dc.subject Medicina Investigació
dc.subject Medicina
dc.subject Pàncrees Malalties
dc.title Transcriptional profiling reveals functional links between RasGrf1 and Pttg1 in pancreatic beta cells
dc.type journal article es_ES
dc.date.updated 2014-12-19T10:50:23Z
dc.identifier.doi 10.1186/1471-2164-15-1019
dc.identifier.idgrec 100574
dc.rights.accessRights open access es_ES

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