ABSTRACT
Transcriptional activity relies on coregulators that modify the chromatin structure and serve as bridging factors between transcription factors and the basal transcription machinery. Using the DE domain of human peroxisome proliferator-activated receptor gamma (PPARgamma) as bait in a yeast two-hybrid screen of a human adipose tissue library, we isolated the scaffold attachment factor B1 (SAFB1/HET/HAP), which was previously shown to be a corepressor of estrogen receptor alpha. We show here that SAFB1 has a very broad tissue expression profile in human and is also expressed all along mouse embryogenesis. SAFB1 interacts in pull-down assays not only with PPARgamma but also with all nuclear receptors tested so far, albeit with different affinities. The association of SAFB1 and PPARgamma in vivo is further demonstrated by fluorescence resonance energy transfer (FRET) experiments in living cells. We finally show that SAFB1 is a rather general corepressor for nuclear receptors. Its change in expression during the early phases of adipocyte and enterocyte differentiation suggests that SAFB1 potentially influences cell proliferation and differentiation decisions.
Subject(s)
Matrix Attachment Region Binding Proteins/metabolism , Nuclear Matrix-Associated Proteins/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Estrogen/metabolism , Adipocytes/metabolism , Animals , Base Sequence , COS Cells , Cell Line , Chlorocebus aethiops , DNA, Complementary/genetics , Embryonic Development/genetics , Female , Humans , In Vitro Techniques , Male , Matrix Attachment Region Binding Proteins/genetics , Mice , Nuclear Matrix-Associated Proteins/genetics , PPAR gamma/metabolism , Pregnancy , Receptors, Estrogen/genetics , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Repressor Proteins/genetics , Repressor Proteins/metabolism , Tissue Distribution , Transcription, Genetic , Two-Hybrid System TechniquesABSTRACT
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors, initially described as molecular targets for synthetic compounds inducing peroxisome proliferation. PPAR-gamma, the best characterized of the PPARs, plays a crucial role in adipogenesis and insulin sensitization. Furthermore, PPAR-gamma has been reported to affect cell proliferation/differentiation pathways in various malignancies. We discuss in the present review recent advances in the understanding of the function of PPAR-gamma in both cell proliferation and adipocyte differentiation.
Subject(s)
Adipose Tissue/cytology , Cell Transformation, Neoplastic , Receptors, Cytoplasmic and Nuclear/physiology , Transcription Factors/physiology , Animals , Cell Differentiation/physiology , Cell Division/physiology , HumansABSTRACT
The peroxisome proliferator-activated receptor gamma is a nuclear hormone receptor playing a crucial role in adipogenesis and insulin sensitization. Prostaglandin J2 derivatives and the antidiabetic thiazolidinediones are its respective natural and synthetic ligands. The RXR/PPAR gamma heterodimer has also been reported to have important immunomodulatory activities and its pleiotropic functions suggest wide-ranging medical implications.
Subject(s)
Adipose Tissue/metabolism , Insulin/physiology , Prostaglandin D2/analogs & derivatives , Receptors, Cytoplasmic and Nuclear/physiology , Thiazolidinediones , Transcription Factors/physiology , Animals , Arteriosclerosis/etiology , Gene Expression , Humans , Inflammation/etiology , Ligands , Prostaglandin D2/analysis , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolism , Thiazoles , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors, initially described as molecular targets for synthetic compounds that induce peroxisome proliferation. PPARgamma is the best characterized of the PPARs. The heterodimer of PPARgamma with the retinoid X receptor (RXR) plays a crucial role in adipogenesis and insulin sensitization. The RXR/PPARgamma heterodimer furthermore has been reported to have important immunomodulatory activities and to affect cell proliferation/differentiation pathways in various malignancies. PPARgamma is activated by a number of naturally occurring fatty acid derivatives and by several synthetic compounds, including the thiazolidinediones and L-tyrosine-based insulin sensitizers. This review gives an overview of the pleiotropic functions of PPARgamma and discusses the wide-ranging medical implications that modulation of PPARgamma activity might have for various diseases, ranging from obesity and type 2 diabetes to cancer and inflammation.
