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PMID:19066220

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Citation

Nofsinger, RR, Li, P, Hong, SH, Jonker, JW, Barish, GD, Ying, H, Cheng, SY, Leblanc, M, Xu, W, Pei, L, Kang, YJ, Nelson, M, Downes, M, Yu, RT, Olefsky, JM, Lee, CH and Evans, RM (2008) SMRT repression of nuclear receptors controls the adipogenic set point and metabolic homeostasis. Proc. Natl. Acad. Sci. U.S.A. 105:20021-6

Abstract

The nuclear receptor corepressor, silencing mediator of retinoid and thyroid hormone receptors (SMRT), is recruited by a plethora of transcription factors to mediate lineage and signal-dependent transcriptional repression. We generated a knockin mutation in the receptor interaction domain (RID) of SMRT (SMRT(mRID)) that solely disrupts its interaction with nuclear hormone receptors (NHRs). SMRT(mRID) mice are viable and exhibit no gross developmental abnormalities, demonstrating that the reported lethality of SMRT knockouts is determined by non-NHR transcription factors. However, SMRT(mRID) mice exhibit widespread metabolic defects including reduced respiration, altered insulin sensitivity, and 70% increased adiposity. The latter phenotype is illustrated by the observation that SMRT(mRID)-derived MEFs display a dramatically increased adipogenic capacity and accelerated differentiation rate. Collectively, our results demonstrate that SMRT-RID-dependent repression is a key determinant of the adipogenic set point as well as an integrator of glucose metabolism and whole-body metabolic homeostasis.

Links

PubMed PMC2598729 Online version:10.1073/pnas.0811012105

Keywords

Adipogenesis/genetics; Animals; Chromatin Immunoprecipitation; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Down-Regulation; Gene Expression Regulation; Gene Knock-In Techniques; Genes, Lethal; Glucose/metabolism; Homeostasis/genetics; Mice; Mice, Mutant Strains; Nuclear Receptor Co-Repressor 2; PPAR gamma/metabolism; Protein Structure, Tertiary; Repressor Proteins/genetics; Repressor Proteins/metabolism; Thyroid Hormone Receptors alpha/genetics; Thyroid Hormone Receptors beta/genetics; Thyroid Hormones/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:PPARG

enables

GO:0003682: chromatin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:PPARG

involved_in

GO:0045444: fat cell differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1337080

P

Seeded From UniProt

complete

MOUSE:PPARG

involved_in

GO:0045444: fat cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NCOR2

enables

GO:0003682: chromatin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:NCOR2

involved_in

GO:0045599: negative regulation of fat cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3829987

P

Seeded From UniProt

complete

MOUSE:NCOR2

involved_in

GO:0050872: white fat cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3829987

P

Seeded From UniProt

complete

MOUSE:NCOR2

involved_in

GO:0042593: glucose homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3829987

P

Seeded From UniProt

complete

MOUSE:PPARG

acts_upstream_of_or_within

GO:0045444: fat cell differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1337080

P

Seeded From UniProt

complete

MOUSE:PPARG

acts_upstream_of_or_within

GO:0045444: fat cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

regulates_o_results_in_acquisition_of_features_of:(CL:0000136)

Seeded From UniProt

complete

MOUSE:PPARG

enables

GO:0003682: chromatin binding

ECO:0000314: direct assay evidence used in manual assertion

F

has_participant:(MGI:MGI:88038)

Seeded From UniProt

complete


See also

References

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