| First Author | Moore BD | Year | 2016 |
| Journal | J Biol Chem | Volume | 291 |
| Issue | 12 | Pages | 6146-57 |
| PubMed ID | 26792861 | Mgi Jnum | J:320681 |
| Mgi Id | MGI:6873328 | Doi | 10.1074/jbc.M115.685750 |
| Citation | Moore BD, et al. (2016) Transcriptional Regulation of X-Box-binding Protein One (XBP1) by Hepatocyte Nuclear Factor 4alpha (HNF4Alpha) Is Vital to Beta-cell Function. J Biol Chem 291(12):6146-57 |
| abstractText | The transcription factor, X-box-binding protein-1 (XBP1), controls the development and maintenance of the endoplasmic reticulum (ER) in multiple secretory cell lineages. We show here that Hepatocyte Nuclear Factor 4alpha (HNF4alpha) directly induces XBP1 expression. Mutations in HNF4alpha cause Mature-Onset Diabetes of the Young I (MODYI), a subset of diabetes characterized by diminished GSIS. In mouse models, cell lines, and ex vivo islets, using dominant negative and human- disease-allele point mutants or knock-out and knockdown models, we show that disruption of HNF4alpha caused decreased expression of XBP1 and reduced cellular ER networks. GSIS depends on ER Ca(2+) signaling; we show that diminished XBP1 and/or HNF4alpha in beta-cells led to impaired ER Ca(2+) homeostasis. Restoring XBP1 expression was sufficient to completely rescue GSIS in HNF4alpha-deficient beta-cells. Our findings uncover a transcriptional relationship between HNF4alpha and Xbp1 with potentially broader implications about MODYI and the importance of transcription factor signaling in the regulation of secretion. |
