scholarly journals T-Cell Factor 4N (TCF-4N), a Novel Isoform of Mouse TCF-4, Synergizes with β-Catenin To Coactivate C/EBPα and Steroidogenic Factor 1 Transcription Factors

2003 ◽  
Vol 23 (15) ◽  
pp. 5366-5375 ◽  
Author(s):  
Jennifer A. Kennell ◽  
Erin E. O'Leary ◽  
Brian M. Gummow ◽  
Gary D. Hammer ◽  
Ormond A. MacDougald
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
Ectopic Expression ◽  
Orphan Nuclear Receptor ◽  
Interaction Domain ◽  
Steroidogenic Factor 1 ◽  
T Cell Factor ◽  
Enhancer Binding Protein ◽  
Physical Interactions ◽  
Adipogenic Transcription Factor

ABSTRACT We have cloned T-cell factor 4N (TCF-4N), an alternative isoform of TCF-4, from developing pituitary and 3T3-L1 preadipocytes. This protein contains the N-terminal interaction domain for β-catenin but lacks the DNA binding domain. While TCF-4N inhibited coactivation by β-catenin of a TCF/lymphoid-enhancing factor (LEF)-dependent promoter, TCF-4N potentiated coactivation by β-catenin of several non-TCF/LEF-dependent promoters. For example, TCF-4N synergized with β-catenin to activate the α-inhibin promoter through functional and physical interactions with the orphan nuclear receptor steroidogenic factor 1 (SF-1). In addition, TCF-4N and β-catenin synergized with the adipogenic transcription factor CCAAT/enhancer binding protein α (C/EBPα) to induce leptin promoter activity. The mechanism by which β-catenin and TCF-4N coactivated C/EBPα appeared to involve p300, based upon synergy between these important transcriptional regulators. Consistent with TCF-4N′s redirecting the actions of β-catenin in cells, ectopic expression of TCF-4N in 3T3-L1 preadipocytes partially relieved the block of adipogenesis caused by β-catenin. Thus, we propose that TCF-4N inhibits coactivation by β-catenin of TCF/LEF transcription factors and potentiates the coactivation by β-catenin of other transcription factors, such as SF-1 and C/EBPα.

scholarly journals Testosterone Inhibits Adipogenic Differentiation in 3T3-L1 Cells: Nuclear Translocation of Androgen Receptor Complex with β-Catenin and T-Cell Factor 4 May Bypass Canonical Wnt Signaling to Down-Regulate Adipogenic Transcription Factors

Endocrinology ◽  
2006 ◽  
Vol 147 (1) ◽  
pp. 141-154 ◽  
Author(s):  
Rajan Singh ◽  
Jorge N. Artaza ◽  
Wayne E. Taylor ◽  
Melissa Braga ◽  
Xin Yuan ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
T Cell ◽  
Wnt Signaling ◽  
Fat Mass ◽  
Nuclear Translocation ◽  
Adipogenic Differentiation ◽  
Inhibitory Effects ◽  
T Cell Factor ◽  
Enhancer Binding Protein ◽  
Canonical Wnt

Testosterone supplementation in men decreases fat mass; however, the mechanisms by which it inhibits fat mass are unknown. We hypothesized that testosterone inhibits adipogenic differentiation of preadipocytes by activation of androgen receptor (AR)/β-catenin interaction and subsequent translocation of this complex to the nucleus thereby bypassing canonical Wnt signaling. We tested this hypothesis in 3T3-L1 cells that differentiate to form fat cells in adipogenic medium. We found that these cells express AR and that testosterone and dihydrotestosterone dose-dependently inhibited adipogenic differentiation as analyzed by Oil Red O staining and down-regulation of CCAAT/enhancer binding protein-α and -δ and peroxisome proliferator-activated receptor-γ2 protein and mRNA. These inhibitory effects of androgens were partially blocked by flutamide or bicalutamide. Androgen treatment was associated with nuclear translocation of β-catenin and AR. Immunoprecipitation studies demonstrated association of β-catenin with AR and T-cell factor 4 (TCF4) in the presence of androgens. Transfection of TCF4 cDNA inhibited adipogenic differentiation, whereas a dominant negative TCF4 cDNA construct induced adipogenesis and blocked testosterone’s inhibitory effects. Our gene array analysis indicates that testosterone treatment led to activation of some Wnt target genes. Expression of constitutively activated AR fused with VP-16 did not inhibit the expression of CCAAT/enhancer binding protein-α in the absence of androgens. Testosterone and dihydrotestosterone inhibit adipocyte differentiation in vitro through an AR-mediated nuclear translocation of β-catenin and activation of downstream Wnt signaling. These data provide evidence for a regulatory role for androgens in inhibiting adipogenic differentiation and a mechanistic explanation consistent with the observed reduction in fat mass in men treated with androgens.

scholarly journals Transcriptional cooperation between NF-κB p50 and CCAAT/enhancer binding protein β regulates Nur77 transcription in Leydig cells

2008 ◽  
Vol 42 (2) ◽  
pp. 131-138 ◽  
Author(s):  
Bassam El-Asmar ◽  
Xavier C Giner ◽  
Jacques J Tremblay
Keyword(s):  
Transcription Factors ◽  
Leydig Cells ◽  
Binding Protein ◽  
Site Directed Mutagenesis ◽  
Orphan Nuclear Receptor ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein ◽  
Cell Gene Expression ◽  
Factor C ◽  
And Function

Expression of steroidogenic enzyme-encoding genes in testicular Leydig cells is complex and involves several transcription factors including the orphan nuclear receptor NUR77 (NR4A1) and the bZIP factor CCAAT/enhancer binding protein β (EBPβ). How these transcription factors are integrated into a functional network, however, remains to be fully understood. Here, we report that the transcription factor C/EBPβ can activate the Nur77 promoter as revealed by transient transfections in MA-10 Leydig cells. Through 5′ progressive deletions and site-directed mutagenesis, the C/EBPβ-mediated activation of the Nur77 promoter was found to be dependent on a novel species-conserved C/EBP element located at −110 bp. We also demonstrate using electromobility shift assay that C/EBPβ specifically binds to this element. Furthermore, we report a functional cooperation between C/EBPβ and the p50 subunit of NF-κB that involves a previously uncharacterized κB element located at −18 bp. Promoter analysis revealed that either the C/EBP or the κB element was sufficient to sustain the C/EBPβ-p50 cooperation thus suggesting that both factors physically interact. Altogether, our results provide new data regarding Nur77 transcription in testicular Leydig cells in addition to providing new insights into the interplay between transcription factors involved in Leydig cell gene expression and function.

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