Overexpression and Ribozyme-mediated Targeting of Transcriptional Coactivators CREB-binding Protein and p300 Revealed Their Indispensable Roles in Adipocyte Differentiation through the Regulation of Peroxisome Proliferator-activated Receptor γ

Takahashi, Nobuyuki; Kawada, Teruo; Yamamoto, Takayuki; Goto, Tsuyoshi; Taimatsu, Aki; Aoki, Naohito; Kawasaki, Hiroaki; Taira, Kazunari; Yokoyama, Kazunari K.; Kamei, Yasutomi; Fushiki, Tohru

doi:10.1074/jbc.m200585200

Cited by 135 publications

(120 citation statements)

References 44 publications

Supporting

Mentioning

115

Contrasting

Unclassified

Order By: Relevance

“…50 Upon induction of differentiation, pRB phosporylation results in its inactivation and HDAC1 is dislodged from PPARg which is now free to bind CBP/p300 and a number of other coactivators. 81,94,95,100 In the early phases of differentiation, increased amounts of PPARg displace HDAC1 from C/EBPb allowing the factor to recruit the SWI/SNF remodeling complex and stimulate transcription of cebpa. 83 Glucocorticoids have the same effect by stimulating C/EBPb acetylation by GCN5.…”

Section: Differentiation Of Preadipocytesmentioning

confidence: 99%

“…81,93,94 Downregulation of CBP/p300 expression significantly reduces adipocyte differentiation. 93,95 Similarly, coexpression of HAT SRC1 with PPARg enhances the transcriptional activity of the factor and adipogenesis, whereas coexpression of corepressor NCoR suppresses it. 96 In 3T3-L1 cells, addition of PPARg ligands breaks the PPARg/ NCoR complex and results in activation of PPARg transcriptional activity.…”

mentioning

confidence: 99%

See 1 more Smart Citation

A chromatin perspective of adipogenesis

2010

View full text Add to dashboard Cite

Section: Differentiation Of Preadipocytesmentioning

confidence: 99%

mentioning

confidence: 99%

A chromatin perspective of adipogenesis

2010

View full text Add to dashboard Cite

“…Helix 12 contributes to the conformational change necessary for cofactor recruitment, a requirement for ligand-dependent activation [7,8] or ligand-independent repression [9] of transcription. PPARγ has been reported to recruit cofactors to activate or repress transcription, including SMRT [10,11], CBP/p300 [12,13], SRC-1 [8], PBP/TRAP220 [14,15], and PGC-1 [16].…”

mentioning

confidence: 99%

“…Additional evidence indicates that cofactor availability to PPARγ is also important in the regulation of adipogenesis. For example, ribozymemediated depletion of CREB-binding protein (CBP) inhibits adipocyte differentiation [13], and ectopic expression of PPARγ in TRAP220 null fibroblasts does not induce adipogenesis [15].…”

mentioning

confidence: 99%

A dominant negative PPARγ mutant shows altered cofactor recruitment and inhibits adipogenesis in 3T3-L1 cells

et al. 2003

View full text Add to dashboard Cite

Aims/hypothesis. PPARγ, a member of the nuclear hormone receptor family of transcription factors, plays a key role in adipocyte differentiation and insulin sensitivity. The aim of this study was to identify a potential dominant negative murine PPARγ mutant and to characterize the in vitro functional properties of this mutant. Methods. In vitro transient transfections and mammalian two-hybrid assays in TSA201 cells were used to characterize the transcriptional activity of the L466A mutant and to study the molecular interaction of transcriptional cofactors with the L466A mutant in an attempt to elucidate the mechanism of its dominant negative activity. Adenoviral constructs expressing PPARγ wild-type (AdWT) or the L466A mutant (AdL466A) were infected into the murine 3T3-L1 cell line to study the mutant's effect on adipogenesis. Results. The L466A mutant alone is transcriptionally defective. However, it retains DNA binding and inhibits the ligand-dependent and -independent activity of the wild-type receptor, consistent with dominant negative properties. In mammalian two-hybrid studies, the L466A mutant does not bind nuclear receptor coactivators. However, it more avidly recruits corepressors due to enhanced binding to the corepressor ID1 domain, leading to pronounced transcriptional repression. The AdL466A mutant inhibits adipogenesis induced by either a differentiation cocktail or by thiazolidinedione ligand. AdL466A infection also blocked the upregulation of the adipocyte marker genes aP2 and adipsin. Conclusion. We conclude that the L466A PPARγ mutant possesses potent dominant negative activity based on preferential corepressor recruitment and it inhibits adipogenesis and the expression of adipocyte-specific genes. [Diabetologia (2003) 46:365-377]

show abstract

“…Thus, induction of high level PPAR␥ expression in fibroblasts requires recruitment of SWI/SNF to its hyperacetylated promoter (22). PPAR␥, in its turn, recruits to its target promoters the histone acetyltransferases CREB-binding protein and p300, and this interaction is essential for adipocyte differentiation (23,24). On the other hand, the retinoblastoma protein RB is associated with the histone deacetylase HDAC3 and blocks adipogenesis in cycling fibroblasts by binding to PPAR␥, thus resulting in recruitment of deacetylase activity to the target promoters of the factor (25) and inhibition of adipogenic gene expression.…”

mentioning

confidence: 99%

Histone H3 Lysine 4 Dimethylation Signals the Transcriptional Competence of the Adiponectin Promoter in Preadipocytes

Musri

Corominola

Casamitjana

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Adipogenesis is regulated by a coordinated cascade of sequencespecific transcription factors and coregulators with chromatinmodifying activities that are between them responsible for the establishment of the gene expression pattern of mature adipocytes. Here we examine the histone H3 post-translational modifications occurring at the promoters of key adipogenic genes during adipocyte differentiation. We show that the promoters of apM1, glut4, gpd1, and leptin are enriched in dimethylated histone H3 Lys 4 (H3-K4) in 3T3-L1 fibroblasts, where none of these genes are yet expressed. A detailed study of the apM1 locus shows that H3-K4 dimethylation is restricted to the promoter region in undifferentiated cells and associates with RNA polymerase II (pol II) loading. The beginning of apM1 transcription at the early stages of adipogenesis coincides with promoter H3 hyperacetylation and H3-K4 trimethylation. At the coding region, H3 acetylation and dimethylation, as well as pol II binding, are found in cells at later stages of differentiation, when apM1 transcription reaches its maximal peak. This same pattern of histone modifications is detected in mouse primary preadipocytes and adipocytes but not in a related fibroblast cell line that is not committed to an adipocyte fate. Inhibition of H3-K4 methylation by treatment of 3T3-L1 cells with methylthioadenosine results in decreased apM1 gene expression as well as decreased adipogenesis. Taken together, our data indicate that H3-K4 dimethylation and pol II binding to the promoter of key adipogenic genes are distinguishing marks of cells that have undergone determination to a preadipocyte stage.The influence exerted by the post-translational modifications of histones over the regulation of gene expression has been extensively studied in the past few years. Numerous studies have shown a clear link between the pattern of histone modifications found at promoter regions and gene transcription, thus leading to the statement of the histone code hypothesis (1), which postulates that the pattern of histone post-translational modifications in a locus considerably extends the amount of information conveyed by the genomic code. Histone H3 and H4 hyperacetylation in promoter regions is closely correlated with gene activation in organisms ranging from yeast to mammals, and transcriptionally active euchromatin regions are highly enriched in acetylated histones (1-5). Unlike acetylation, histone H3 methylation can be equally associated with either transcriptional activation or repression. Methylation of the lysine residue Lys 4 of histone H3 (H3-K4) 3 correlates with activation of gene expression in most systems (2, 4 -7), whereas H3 Lys 9 (H3-K9) methylation is involved in the establishment and maintenance of silent heterochromatin regions (8). Moreover, lysine residues can be mono-, di-, or trimethylated in vivo, thus providing a further layer of complexity and exponentially increasing functional diversity (9, 10). The recent identification of LSD1, the first histone demethylase to be ch...

show abstract

Overexpression and Ribozyme-mediated Targeting of Transcriptional Coactivators CREB-binding Protein and p300 Revealed Their Indispensable Roles in Adipocyte Differentiation through the Regulation of Peroxisome Proliferator-activated Receptor γ

Cited by 135 publications

References 44 publications

A chromatin perspective of adipogenesis

A chromatin perspective of adipogenesis

A dominant negative PPARγ mutant shows altered cofactor recruitment and inhibits adipogenesis in 3T3-L1 cells

Histone H3 Lysine 4 Dimethylation Signals the Transcriptional Competence of the Adiponectin Promoter in Preadipocytes

Contact Info

Product

Resources

About