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

Bonnefond, Amelie, Lomberk, Gwen, Buttar, Navtej, Busiah, Kanetee, Vaillant, Emmanuel, Lobbens, Stephane, Yengo, Loic, Dechaume, Aurelie, Mignot, Brigitte, Simon, Albane, Scharfmann, Raphael, Neve, Bernadette, Tanyolac, Sinan, Hodoglugil, Ugur, Pattou, Francois, Cave, Helene, Iovanna, Juan, Stein, Roland, Polak, Michel, Vaxillaire, Martine, Froguel, Philippe and Urrutia, Raul (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. doi:10.1074/jbc.M110.215822

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Author Bonnefond, Amelie
Lomberk, Gwen
Buttar, Navtej
Busiah, Kanetee
Vaillant, Emmanuel
Lobbens, Stephane
Yengo, Loic
Dechaume, Aurelie
Mignot, Brigitte
Simon, Albane
Scharfmann, Raphael
Neve, Bernadette
Tanyolac, Sinan
Hodoglugil, Ugur
Pattou, Francois
Cave, Helene
Iovanna, Juan
Stein, Roland
Polak, Michel
Vaxillaire, Martine
Froguel, Philippe
Urrutia, Raul
Title 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
Formatted title
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 name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
1083-351X
Publication date 2011-08-12
Sub-type Article (original research)
DOI 10.1074/jbc.M110.215822
Open Access Status File (Publisher version)
Volume 286
Issue 32
Start page 28414
End page 28424
Total pages 11
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Formatted 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.
Keyword Diabetes
Genetic diseases
Glucose metabolism
Pancreatic Islet
Transcription regulation
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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