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

Amélie Bonnefond, Gwen Lomberk, Navtej Buttar, Kanetee Busiah, Emmanuel Vaillant, Stéphane Lobbens, Loïc Yengo, Aurélie Dechaume, Brigitte Mignot, Albane Simon, Raphaël Scharfmann, Bernadette Neve, Sinan Tanyolaç, Ugur Hodoglugil, François Pattou, Hélène Cavé, Juan Iovanna, Roland Stein, Michel Polak, Martine VaxillairePhilippe Froguel, Raul Urrutia

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)28414-28424
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number32
DOIs
StatePublished - Aug 12 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    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., ... Urrutia, R. (2011). 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. Journal of Biological Chemistry, 286(32), 28414-28424. https://doi.org/10.1074/jbc.M110.215822