Involvement of Per-Arnt-Sim (PAS) kinase in the stimulation of preproinsulin and pancreatic duodenum homeobox 1 gene expression by glucose

Research output: Contribution to journalArticle

Authors

Colleges, School and Institutes

Abstract

Per-Arnt-Sim (PAS) domain-containing kinases are common in prokaryotes, but a mammalian counterpart has only recently been described. Although the PAS domain of the mammalian PAS kinase (PASK) is closely related to the bacterial oxygen sensor FixL, it is unclear whether PASK activity is changed in mammalian cells in response to nutrients and might therefore contribute to signal transduction by these or other stimuli. Here, we show that elevated glucose concentrations rapidly increase PASK activity in pancreatic islet beta cells, an event followed by the accumulation of both PASK mRNA and protein. Demonstrating a physiological role for PASK activation, comicroinjection into clonal beta cells of cDNA encoding wild-type PASK, or PASK protein itself, mimics the induction of preproinsulin promoter activity by high glucose concentrations. Conversely, anti-PASK antibodies block promoter activation by the sugar, and the silencing of PASK expression by RNA interference suppresses the up-regulation by glucose of preproinsulin and pancreatic duodenum homeobox 1 gene expression, without affecting glucose-induced changes in the levels of mRNAs encoding glucokinase or uncoupling protein 2. We conclude that PASK is an important metabolic sensor in nutrient-sensitive mammalian cells and plays an unexpected role in the regulation of key genes involved in maintaining the differentiated phenotype of pancreatic beta cells.

Details

Original languageEnglish
Pages (from-to)8319-24
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number22
Publication statusPublished - 1 Jun 2004

Keywords

  • Adenosine Triphosphate/metabolism, Animals, Cell Line, Culture Techniques, Gene Expression Regulation, Genes, Reporter, Glucose/metabolism, Homeodomain Proteins, Human Growth Hormone/genetics, Humans, Insulin, Islets of Langerhans/cytology, Proinsulin/genetics, Promoter Regions, Genetic, Protein Precursors/genetics, Protein-Serine-Threonine Kinases/genetics, RNA, Small Interfering/metabolism, Rats, Trans-Activators/genetics