Anks4b, a novel target of HNF4? protein, interacts with GRP78 protein and regulates endoplasmic reticulum stress-induced apoptosis in pancreatic ?-cells.

ABSTRACT: Mutations of the HNF4A gene cause a form of maturity-onset diabetes of the young (MODY1) that is characterized by impairment of pancreatic ?-cell function. HNF4? is a transcription factor belonging to the nuclear receptor superfamily (NR2A1), but its target genes in pancreatic ?-cells are largely unknown. Here, we report that ankyrin repeat and sterile ? motif domain containing 4b (Anks4b) is a target of HNF4? in pancreatic ?-cells. Expression of Anks4b was decreased in both ?HNF4? KO islets and HNF4? knockdown MIN6 ?-cells, and HNF4? activated Anks4b promoter activity. Anks4b bound to glucose-regulated protein 78 (GRP78), a major endoplasmic reticulum (ER) chaperone protein, and overexpression of Anks4b enhanced the ER stress response and ER stress-associated apoptosis of MIN6 cells. Conversely, suppression of Anks4b reduced ?-cell susceptibility to ER stress-induced apoptosis. These results indicate that Anks4b is a HNF4? target gene that regulates ER stress in ?-cells by interacting with GRP78, thus suggesting that HNF4? is involved in maintenance of the ER.

SUBMITTER: Sato Y 

PROVIDER: S-EPMC3391104 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature