title: Anks4b, a novel target of HNF4α protein, interacts with GRP78 protein and regulates endoplasmic reticulum stress-induced apoptosis in pancreatic β-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 β-cell function. HNF4α is a transcription factor belonging to the nuclear receptor superfamily (NR2A1), but its target genes in pancreatic β-cells are largely unknown. Here, we report that ankyrin repeat and sterile α motif domain containing 4b (Anks4b) is a target of HNF4α in pancreatic β-cells. Expression of Anks4b was decreased in both βHNF4α KO islets and HNF4α knockdown MIN6 β-cells, and HNF4α 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 β-cell susceptibility to ER stress-induced apoptosis. These results indicate that Anks4b is a HNF4α target gene that regulates ER stress in β-cells by interacting with GRP78, thus suggesting that HNF4α is involved in maintenance of the ER.
authors.affiliation: Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Sato
authors.forename: Mitsutoki
authors.initials: M
authors.lastname: Hatta
authors.forename: Md Fazlul
authors.initials: MF
authors.lastname: Karim
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Sawa
authors.forename: Fan-Yan
authors.initials: FY
authors.lastname: Wei
authors.forename: Shoki
authors.initials: S
authors.lastname: Sato
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Tomizawa
authors.forename: Takaaki
authors.initials: T
authors.lastname: Akaike
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yoshizawa
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yamagata
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D006360:Heat-Shock Proteins / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D007340:Insulinoma; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms; D040901:Proteomics; D015533:Transcriptional Activation / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C499676:Harp (harmonin-interacting) protein, mouse; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins