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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Non-DNA binding, dominant-negative, human PPARγ mutations cause lipodystrophic insulin resistance
Cell Metabolism, Volume 4, No. 4, Year 2006
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Description
PPARγ is essential for adipogenesis and metabolic homeostasis. We describe mutations in the DNA and ligand binding domains of human PPARγ in lipodystrophic, severe insulin resistance. These receptor mutants lack DNA binding and transcriptional activity but can translocate to the nucleus, interact with PPARγ coactivators and inhibit coexpressed wild-type receptor. Expression of PPARγ target genes is markedly attenuated in mutation-containing versus receptor haploinsufficent primary cells, indicating that such dominant-negative inhibition operates in vivo. Our observations suggest that these mutants restrict wild-type PPARγ action via a non-DNA binding, transcriptional interference mechanism, which may involve sequestration of functionally limiting coactivators. © 2006 Elsevier Inc. All rights reserved.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC1821092/bin/mmc1.pdf
Authors & Co-Authors
Agostini, Maura
United Kingdom, Cambridge
University of Cambridge
Schoenmakers, Erik
United Kingdom, Cambridge
University of Cambridge
Mitchell, Catherine
United Kingdom, Cambridge
University of Cambridge
Szatmari, Istvan
Hungary, Debrecen
Debreceni Egyetem
Savage, David Bousfield
United Kingdom, Cambridge
University of Cambridge
Smith, Aaron
United Kingdom, Cambridge
University of Cambridge
Rajanayagam, Odelia
United Kingdom, Cambridge
University of Cambridge
Semple, Robert K.
United Kingdom, Cambridge
University of Cambridge
Luan, Jian'fan N.An
United Kingdom, Cambridge
Mrc Epidemiology Unit
Bath, Louise
United Kingdom, Edinburgh
Royal Hospital for Sick Children
Zalin, Anthony
United Kingdom
Wordsley Hospital
Labib, Mourad
United Kingdom
Wordsley Hospital
Kumar, Sudhesh
United Kingdom, Coventry
University of Warwick
Simpson, Helen
United Kingdom, Cambridge
University of Cambridge
Blom, Dirk J.
South Africa, Cape Town
University of Cape Town
Marais, David A.
South Africa, Cape Town
University of Cape Town
Schwabe, John
United Kingdom, Cambridge
The Medical Research Council Laboratory of Molecular Biology
Barroso, Inês E.
United Kingdom, Hinxton
Wellcome Sanger Institute
Trembath, Richard C.
United Kingdom, London
King's College London
Wareham, Nicholas J.
United Kingdom, Cambridge
Mrc Epidemiology Unit
Nagy, Laszlo
Hungary, Debrecen
Debreceni Egyetem
Gurnell, Mark
United Kingdom, Cambridge
University of Cambridge
O'Rahilly, Stephen P.
United Kingdom, Cambridge
University of Cambridge
Chatterjee, V. Krishna
United Kingdom, Cambridge
University of Cambridge
Statistics
Citations: 179
Authors: 24
Affiliations: 10
Identifiers
Doi:
10.1016/j.cmet.2006.09.003
ISSN:
15504131
Research Areas
Cancer
Genetics And Genomics
Noncommunicable Diseases