MED25 is a mediator component of HNF4α-driven transcription leading to insulin secretion in pancreatic beta-cells. PLoS One 2012;7(8):e44007
Date
09/07/2012Pubmed ID
22952853Pubmed Central ID
PMC3431373DOI
10.1371/journal.pone.0044007Scopus ID
2-s2.0-84865598963 (requires institutional sign-in at Scopus site) 13 CitationsAbstract
Unique nuclear receptor Hepatocyte Nuclear Factor 4α (HNF4α) is an essential transcriptional regulator for early development and proper function of pancreatic ß-cells, and its mutations are monogenic causes of a dominant inherited form of diabetes referred to as Maturity Onset Diabetes of the Young 1 (MODY1). As a gene-specific transcription factor, HNF4α exerts its function through various molecular interactions, but its protein recruiting network has not been fully characterized. Here we report the identification of MED25 as one of the HNF4α binding partners in pancreatic ß-cells leading to insulin secretion which is impaired in MODY patients. MED25 is one of the subunits of the Mediator complex that is required for induction of RNA polymerase II transcription by various transcription factors including nuclear receptors. This HNF4α-MED25 interaction was initially identified by a yeast-two-hybrid method, confirmed by in vivo and in vitro analyses, and proven to be mediated through the MED25-LXXLL motif in a ligand-independent manner. Reporter-gene based transcription assays and siRNA/shRNA-based gene silencing approaches revealed that this interaction is crucial for full activation of HNF4α-mediated transcription, especially expression of target genes implicated in glucose-stimulated insulin secretion. Selected MODY mutations at the LXXLL motif binding pocket disrupt these interactions and cause impaired insulin secretion through a 'loss-of-function' mechanism.
Author List
Han EH, Rha GB, Chi YIAuthor
Young-In Chi PhD Assistant Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Amino Acid MotifsAnimals
Binding Sites
Diabetes Mellitus, Type 2
Glucose
HeLa Cells
Hepatocyte Nuclear Factor 4
Humans
Insulin
Insulin-Secreting Cells
Mediator Complex
Mice
Models, Molecular
Point Mutation
Protein Binding
Protein Conformation
RNA Interference
Signal Transduction
Transcription, Genetic
Transcriptional Activation
