TY - JOUR
T1 - Disruption of a novel krüppel-like transcription factor p300-regulated pathway for insulin biosynthesis revealed by studies of the c.-331 INS mutation found in neonatal diabetes mellitus
AU - Bonnefond, Amélie
AU - Lomberk, Gwen
AU - Buttar, Navtej
AU - Busiah, Kanetee
AU - Vaillant, Emmanuel
AU - Lobbens, Stéphane
AU - Yengo, Loïc
AU - Dechaume, Aurélie
AU - Mignot, Brigitte
AU - Simon, Albane
AU - Scharfmann, Raphaël
AU - Neve, Bernadette
AU - Tanyolaç, Sinan
AU - Hodoglugil, Ugur
AU - Pattou, François
AU - Cavé, Hélène
AU - Iovanna, Juan
AU - Stein, Roland
AU - Polak, Michel
AU - Vaxillaire, Martine
AU - Froguel, Philippe
AU - Urrutia, Raul
PY - 2011/8/12
Y1 - 2011/8/12
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M110.215822
DO - 10.1074/jbc.M110.215822
M3 - Article
C2 - 21592955
AN - SCOPUS:80051527724
SN - 0021-9258
VL - 286
SP - 28414
EP - 28424
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 32
ER -