Pancreatic and duodenal homeobox protein 1 (Pdx-1) maintains endoplasmic reticulum calcium levels through transcriptional regulation of sarco-endoplasmic reticulum calcium ATPase 2b (SERCA2b) in the islet β cell
dc.contributor.author | Johnson, Justin S. | |
dc.contributor.author | Kono, Tatsuyoshi | |
dc.contributor.author | Tong, Xin | |
dc.contributor.author | Yamamoto, Wataru R. | |
dc.contributor.author | Zarain-Herzberg, Angel | |
dc.contributor.author | Merrins, Matthew J. | |
dc.contributor.author | Satin, Leslie S. | |
dc.contributor.author | Gilon, Patrick | |
dc.contributor.author | Evans-Molina, Carmella | |
dc.contributor.department | Department of Medicine, IU School of Medicine | en_US |
dc.date.accessioned | 2016-10-19T18:15:04Z | |
dc.date.available | 2016-10-19T18:15:04Z | |
dc.date.issued | 2014-11-21 | |
dc.description.abstract | Although the pancreatic duodenal homeobox 1 (Pdx-1) transcription factor is known to play an indispensable role in β cell development and secretory function, recent data also implicate Pdx-1 in the maintenance of endoplasmic reticulum (ER) health. The sarco-endoplasmic reticulum Ca(2+) ATPase 2b (SERCA2b) pump maintains a steep Ca(2+) gradient between the cytosol and ER lumen. In models of diabetes, our data demonstrated loss of β cell Pdx-1 that occurs in parallel with altered SERCA2b expression, whereas in silico analysis of the SERCA2b promoter revealed multiple putative Pdx-1 binding sites. We hypothesized that Pdx-1 loss under inflammatory and diabetic conditions leads to decreased SERCA2b levels and activity with concomitant alterations in ER health. To test this, siRNA-mediated knockdown of Pdx-1 was performed in INS-1 cells. The results revealed reduced SERCA2b expression and decreased ER Ca(2+), which was measured using fluorescence lifetime imaging microscopy. Cotransfection of human Pdx-1 with a reporter fused to the human SERCA2 promoter increased luciferase activity 3- to 4-fold relative to an empty vector control, and direct binding of Pdx-1 to the proximal SERCA2 promoter was confirmed by chromatin immunoprecipitation. To determine whether restoration of SERCA2b could rescue ER stress induced by Pdx-1 loss, Pdx1(+/-) mice were fed a high-fat diet. Isolated islets demonstrated an increased spliced-to-total Xbp1 ratio, whereas SERCA2b overexpression reduced the Xbp1 ratio to that of wild-type controls. Together, these results identify SERCA2b as a novel transcriptional target of Pdx-1 and define a role for altered ER Ca(2+) regulation in Pdx-1-deficient states. | en_US |
dc.identifier.citation | Johnson, J. S., Kono, T., Tong, X., Yamamoto, W. R., Zarain-Herzberg, A., Merrins, M. J., … Evans-Molina, C. (2014). Pancreatic and Duodenal Homeobox Protein 1 (Pdx-1) Maintains Endoplasmic Reticulum Calcium Levels through Transcriptional Regulation of Sarco-endoplasmic Reticulum Calcium ATPase 2b (SERCA2b) in the Islet β Cell. The Journal of Biological Chemistry, 289(47), 32798–32810. http://doi.org/10.1074/jbc.M114.575191 | en_US |
dc.identifier.issn | 1083-351X | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/11192 | |
dc.language.iso | en_US | en_US |
dc.publisher | American Society for Biochemistry and Molecular Biology | en_US |
dc.relation.isversionof | 10.1074/jbc.M114.575191 | en_US |
dc.relation.journal | The Journal of Biological Chemistry | en_US |
dc.rights | Publisher Policy | en_US |
dc.source | PMC | en_US |
dc.subject | Calcium | en_US |
dc.subject | metabolism | en_US |
dc.subject | Endoplasmic Reticulum | en_US |
dc.subject | Homeodomain Proteins | en_US |
dc.subject | genetics | en_US |
dc.subject | Insulin-Secreting Cells | en_US |
dc.subject | Sarcoplasmic Reticulum Calcium-Transporting ATPases | en_US |
dc.subject | Trans-Activators | en_US |
dc.title | Pancreatic and duodenal homeobox protein 1 (Pdx-1) maintains endoplasmic reticulum calcium levels through transcriptional regulation of sarco-endoplasmic reticulum calcium ATPase 2b (SERCA2b) in the islet β cell | en_US |
dc.type | Article | en_US |
ul.alternative.fulltext | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239629/ | en_US |
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