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Por favor, use este identificador para citar o enlazar a este item: http://hdl.handle.net/10261/51097
Título

Hepatic nuclear factor 1α (HNF1α) dysfunction down-regulates X-box-binding protein 1 (XBP1) and sensitizes β-cells to endoplasmic reticulum stress

AutorKirkpatrick, Clare L.; Baquié, Mathurin; Gauthier, Benoit R.; Wollheim, Claes B.
Palabras claveCalcium
Diabetes
ER Stress
Insulin
Pancreatic islets
Fecha de publicación16-sep-2011
EditorAmerican Society for Biochemistry and Molecular Biology
CitaciónJournal of Biological Chemistry 286(37): 32300-32312 (2011)
ResumenCorrect endoplasmic reticulum (ER) function is critical for the health of secretory cells, such as the pancreatic β-cell, and ER stress is often a contributory factor to β-cell death in type 2 diabetes.Wehave used an insulin-secreting cell line with inducible expression of dominant negative (DN) HNF1α, a transcription factor vital for correct β-cell development and function, to show that HNF1α is required for Xbp1 transcription and maintenance of the normal ER stress response. DN HNF1α expression sensitizes the β-cell to ER stress by directly downregulating Xbp1 transcription, whereas Atf6 is unaffected. Furthermore, DN HNF1α alters calcium homeostasis, resulting in elevated cytoplasmic calcium and increased store-operated calcium entry, whereas mitochondrial calcium uptake is normal. Loss of function of XBP1 is toxic to the β-cell and decreases production of the ER chaperone BiP, even in the absence of ER stress. DN HNF1α-induced sensitivity to cyclopiazonic acid can be partially rescued with the chemical chaperone tauroursode-oxycholate. Rat insulin 2 promoter-DN HNF1α mouse islets express lower levels of BiP mRNA, synthesize less insulin, and are sensitized to ER stress relative to matched control mouse islets, suggesting that this mechanism is also operating in vivo.
Descripciónet al.
URIhttp://hdl.handle.net/10261/51097
DOI10.1074/jbc.M111.247866
Identificadoresissn: 0021-9258
e-issn: 1083-351X
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