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Novel repressor regulates insulin sensitivity through interaction with Foxo1.

The EMBO journal | May 16, 2012

Forkhead box-containing protein o (Foxo) 1 is a key transcription factor in insulin and glucose metabolism. We identified a Foxo1-CoRepressor (FCoR) protein in mouse adipose tissue that inhibits Foxo1's activity by enhancing acetylation via impairment of the interaction between Foxo1 and the deacetylase Sirt1 and via direct acetylation. FCoR is phosphorylated at Threonine 93 by catalytic subunit of protein kinase A and is translocated into nucleus, making it possible to bind to Foxo1 in both cytosol and nucleus. Knockdown of FCoR in 3T3-F442A cells enhanced expression of Foxo target and inhibited adipocyte differentiation. Overexpression of FCoR in white adipose tissue decreased expression of Foxo-target genes and adipocyte size and increased insulin sensitivity in Lepr(db/db) mice and in mice fed a high-fat diet. In contrast, Fcor knockout mice were lean, glucose intolerant, and had decreased insulin sensitivity that was accompanied by increased expression levels of Foxo-target genes and enlarged adipocytes. Taken together, these data suggest that FCoR is a novel repressor that regulates insulin sensitivity and energy metabolism in adipose tissue by acting to fine-tune Foxo1 activity.

Pubmed ID: 22510882 RIS Download

Mesh terms: Acetylation | Adipose Tissue | Animals | Co-Repressor Proteins | Forkhead Box Protein O1 | Forkhead Transcription Factors | Gene Expression | Gene Expression Regulation | Gene Knockdown Techniques | Insulin Resistance | Mice | Mice, Knockout | Sirtuin 1

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Eukaryotic Linear Motif

Computational biology resource for investigating candidate functional sites in eukarytic proteins. Functional sites which fit to the description linear motif are currently specified as patterns using Regular Expression rules. To improve the predictive power, context-based rules and logical filters are being developed and applied to reduce the amount of false positives. The current version of the ELM server provides core functionality including filtering by cell compartment, phylogeny, globular domain clash (using the SMART/Pfam databases) and structure. In addition, both the known ELM instances and any positionally conserved matches in sequences similar to ELM instance sequences are identified and displayed (see ELM instance mapper). Although the ELM resource contains a large collection of functional site motifs, the current set of motifs is not exhaustive.


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