Disruption of a novel Kruppel-like transcription factor p300-regulated pathway for insulin biosynthesis revealed by studies of the c.-331 INS mutation found in neonatal diabetes mellitus. J Biol Chem 2011 Aug 12;286(32):28414-24
Date
05/20/2011Pubmed ID
21592955Pubmed Central ID
PMC3151084DOI
10.1074/jbc.M110.215822Scopus ID
2-s2.0-80051527724 (requires institutional sign-in at Scopus site) 68 CitationsAbstract
Krüppel-like transcription factors (KLFs) have elicited significant attention because of their regulation of essential biochemical pathways and, more recently, because of their fundamental role in the mechanisms of human diseases. Neonatal diabetes mellitus is a monogenic disorder with primary alterations in insulin secretion. We here describe a key biochemical mechanism that underlies neonatal diabetes mellitus insulin biosynthesis impairment, namely a homozygous mutation within the insulin gene (INS) promoter, c.-331C>G, which affects a novel KLF-binding site. The combination of careful expression profiling, electromobility shift assays, reporter experiments, and chromatin immunoprecipitation demonstrates that, among 16 different KLF proteins tested, KLF11 is the most reliable activator of this site. Congruently, the c.-331C>G INS mutation fails to bind KLF11, thus inhibiting activation by this transcription factor. Klf11(-/-) mice recapitulate the disruption in insulin production and blood levels observed in patients. Thus, these data demonstrate an important role for KLF11 in the regulation of INS transcription via the novel c.-331 KLF site. Lastly, our screening data raised the possibility that other members of the KLF family may also regulate this promoter under distinct, yet unidentified, cellular contexts. Collectively, this study underscores a key role for KLF proteins in biochemical mechanisms of human diseases, in particular, early infancy onset diabetes mellitus.
Author List
Bonnefond A, Lomberk G, Buttar N, Busiah K, Vaillant E, Lobbens S, Yengo L, Dechaume A, Mignot B, Simon A, Scharfmann R, Neve B, Tanyolaç S, Hodoglugil U, Pattou F, Cavé H, Iovanna J, Stein R, Polak M, Vaxillaire M, Froguel P, Urrutia RAuthors
Gwen Lomberk PhD Professor in the Surgery department at Medical College of WisconsinRaul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdultAnimals
Apoptosis Regulatory Proteins
Cell Cycle Proteins
Cell Line
Child, Preschool
DNA-Binding Proteins
Diabetes Mellitus
Female
Humans
Infant
Infant, Newborn
Infant, Newborn, Diseases
Insulin
Insulin-Secreting Cells
Male
Mice
Mice, Knockout
Mutagenesis, Insertional
Rats
Repressor Proteins
Response Elements
Trans-Activators
Transcription Factors
