Troglitazone Induces Expression of PPARγ in Liver

Davies, Gerald F.; Khandelwal, Ramji L.; Roesler, William J.

doi:10.1006/mcbr.2000.0176

Cited by 31 publications

(29 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PPAR␥ is expressed in hepatocytes, and the expression of PPAR␥ is induced by TZDs in vivo (13). It has been hypothesized that the insulin-sensitizing effects of TZDs may result in part from effects on PPAR␥ expression and function in muscle and liver (12,13). The induction of the GFP from the second cistron of the cyclin D1 antisense transgene was observed by Western blotting (Fig.…”

Section: Resultsmentioning

confidence: 98%

Cyclin D1 Repression of Peroxisome Proliferator-Activated Receptor γ Expression and Transactivation

Wang

Pattabiraman

Zhou³

et al. 2003

Molecular and Cellular Biology

183

181

View full text Add to dashboard Cite

The cyclin D1 gene is overexpressed in human breast cancers and is required for oncogene-induced tumorigenesis. Peroxisome proliferator-activated receptor ␥ (PPAR␥) is a nuclear receptor selectively activated by ligands of the thiazolidinedione class. PPAR␥ induces hepatic steatosis, and liganded PPAR␥ promotes adipocyte differentiation. Herein, cyclin D1 inhibited ligand-induced PPAR␥ function, transactivation, expression, and promoter activity. PPAR␥ transactivation induced by the ligand BRL49653 was inhibited by cyclin D1 through a pRB-and cdk-independent mechanism, requiring a region predicted to form an helix-loop-helix ( The cyclin-dependent kinase holoenzymes are a family of serine/threonine kinases that play a pivotal role in controlling progression through the cell cycle (38,47). Dysregulation of the cell cycle control apparatus is an almost uniform aberration in tumorigenesis (48). The cyclins encode regulatory subunits of the kinases which phosphorylate specific proteins, including the retinoblastoma (pRB) protein, to promote transition through specific cell cycle checkpoints (47, 57). Cyclin D1 plays a pivotal role in G 1 /S phase cell cycle progression in fibroblasts and is rate limiting in growth factor-or estrogen-induced mammary epithelial cell proliferation (29, 67). Cyclin D1 overexpression is found in Ͼ30% of human breast cancers, correlating with poor prognosis (23). Several different oncogenic signals induce cyclin D1 expression, including mutations of the Ras and Wnt/APC/␤-catenin pathway (2, 49). Mammary-targeted expression of cyclin D1 is sufficient for the induction of mammary adenocarcinoma, and cyclin D1 Ϫ/Ϫ mice are resistant to ErbB2-induced tumorigenesis (53,64).In addition to binding cyclin-dependent kinases 4 and 6 (cdk4 and cdk6) and pRB, cyclin D1 forms physical associations with P/CAF (p300/CBP-associated factor), Myb, MyoD, and the cyclin D1 myb-like binding protein (DMP1) (16,20,31,39). Binding of cyclin D1 to the estrogen receptor alpha (ER␣) enhances ligand-independent reporter gene activity, and liganded androgen receptor reporter gene activity is inhibited by cyclin D1 (33, 39, 68). The in vivo or genetic evidence indicating a requirement for cyclin D1 in nuclear receptor function remained to be determined. The peroxisome proliferator-activator receptors, including PPAR␣, PPAR␥, and PPAR␦, are ligand-activated nuclear receptors (42). Their modular structure resembles those of other nuclear hormone receptors with N-terminal AF-1, a DNA binding domain, and a carboxyl-terminal ligand-binding domain (LBD). PPAR␥ was cloned as a transcription factor involved in fat cell differentiation and is required for the induction of adipocyte differentiation (41, 51). Adenoviral delivery of PPAR␥ to the livers of mice induces hepatic steatosis, consistent with an important role for PPAR␥ in hepatocellular lipid biosynthesis (65). The PPAR␥ ligands include eicosanoids, such as 15-deoxy-⌬12,14-prostaglandin J2 (15d-PGJ 2 ), and synthetic ligands of the thiazolidinedione (TZD) class. PPAR␥ ...

show abstract

Section: Resultsmentioning

confidence: 98%

Cyclin D1 Repression of Peroxisome Proliferator-Activated Receptor γ Expression and Transactivation

Wang

Pattabiraman

Zhou³

et al. 2003

Molecular and Cellular Biology

183

181

View full text Add to dashboard Cite

show abstract

“…Davies et al [19] reported that the G6Pase mRNA level in isolated hepatocytes from BB/Zucker obese-diabetic rats was elevated compared to non-diabetic rats and that troglitazone reduced the expression of G6Pase mRNA.…”

Section: Discussionmentioning

confidence: 99%

Dehydroepiandrosterone Suppresses Elevated Hepatic Glucose-6-phosphatase mRNA Level in C57BL/KsJ-db/db Mice. Comparison with Troglitazone.

et al. 2000

View full text Add to dashboard Cite

Abstract.Dehydroepiandrosterone (DHEA) is known to improve hyperglycemia of diabetic C57BL/KsJ-db/db mice that are obese and insulin resistant.In a previous study, we reported that DHEA as well as troglitazone suppresses the elevated hepatic gluconeogenic enzymes, glucose-6-phosphatase (G6Pase) and fructose-l,6-bisphosphatase (FBPase) activities in C57BL/KsJ-db/db mice. In the present study, we evaluated the changes in mRNA of G6Pase and FBPase in db/db mice. Despite hyperinsulinemia, the G6Pase mRNA level of db/db mice was elevated as compared to their heterozygote littermate db/+m mice. In contrast, the FBPase mRNA level was not elevated in db/db mice. Administration of DHEA for two weeks significantly decreased the blood glucose level and the elevated G6Pase mRNA level in db/db mice. No significant changes were seen in the FBPase mRNA level after the administration of DHEA. Administration of troglitazone also decreased the blood glucose and G6Pase mRNA level in db/db mice although no changes were seen in the FBPase mRNA level. These results suggest that the elevation of G6Pase mRNA is important in elucidating the cause of insulin resistance, and that the G6Pase gene is at least one target for the hypoglycemic effects of DHEA as an insulin sensitizing agent in db/db mice.

show abstract

“…Western Blot Analysis-Western blot analysis was performed as previously described (29), using Western Lightning TM chemiluminescent reagent (PerkinElmer Life Sciences) to detect the antigen-antibody complexes. Anti-C/EBP␣ (14AA) was purchased from Santa Cruz Biotechnology (Santa Cruz, CA), anti-CREB antibody (9192) was purchased from Cell Signaling, and anti-CA150 antibodies (BL456) were purchased from Bethyl Laboratories (Montgomery, TX).…”

mentioning

confidence: 99%

Identification of a Co-repressor That Inhibits the Transcriptional and Growth-Arrest Activities of CCAAT/Enhancer-binding Protein α

McFie

Wang

Timchenko

et al. 2006

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

We used a yeast two-hybrid screening approach to identify novel interactors of CCAAT/enhancer-binding protein ␣ (C/EBP␣) that may offer insight into its mechanism of action and regulation. One clone obtained was that for CA150, a nuclear protein previously characterized as a transcriptional elongation factor. In this report, we show that CA150 is a widely expressed co-repressor of C/EBP proteins. Two-hybrid and co-immunoprecipitation analyses indicated that CA150 interacts with C/EBP␣. Overexpression of CA150 inhibited the transactivation produced by C/EBP␣ and was also able to reverse the enhancing effect of the co-activator p300 on C/EBP␤-mediated transactivation. Analysis of C/EBP␣ mutants indicated that CA150 interacts with C/EBP␣ primarily through a domain spanning amino acids 135-150. Chromatin immunoprecipitation assays showed that CA150 was present on a promoter that is repressed by C/EBP␣ but not present on a promoter that is activated by C/EBP␣. Finally, we showed that in cells in which growth arrest had been induced by ectopic expression of C/EBP␣, CA150 was able to release them from growth arrest. Interestingly, CA150 could not reverse the growth arrest produced by the minimal growth-arrest domain of C/EBP␣ (amino acids 175-217), suggesting that the effect of CA150 was directed at a region of C/EBP␣ outside of this minimal domain, consistent with our two-hybrid analysis. Taken together, these data indicate that CA150 is a co-repressor of C/EBP proteins and provides a possible mechanism for how C/EBP␣ can repress transcription of specific genes. CCAAT/enhancer binding proteins (C/EBPs)2 are eukaryotic transcription factors that regulate a large number of genes. There are eight members in the C/EBP protein family, and the first two members that were identified, C/EBP␣ and C/EBP␤, are the most extensively examined and characterized (1). Although they are expressed in a variety of cell types, both family members are enriched in liver and have been demonstrated to regulate the expression of a number of genes that are associated with energy metabolism (2).C/EBP␣ and -␤ have been generally observed to be activators of transcription. The transactivation domains of these proteins reside in the N terminus of each protein, and can function independently of the basic region-leucine zipper DNA-binding domain if linked to a heterologous DNA-binding domain (1). There appear to be several sub-domains within the transactivation domains that mediate transactivation (3)(4)(5)(6)(7)(8), although the precise boundaries of these regions are difficult to determine from the available studies because they are assigned based on the arbitrary design of the mutants used. For C/EBP␣, studies indicate that the majority of the transactivation potential lies within amino acid residues 1-150 (5), whereas for C/EBP␤, the transactivation domain appears to lie within amino acid residues 1-108 (9).In addition to its transcriptional role, C/EBP␣ is also a strong inhibitor of cell proliferation. It inhibits proliferation of cultured cells...

show abstract

Troglitazone Induces Expression of PPARγ in Liver

Cited by 31 publications

References 32 publications

Cyclin D1 Repression of Peroxisome Proliferator-Activated Receptor γ Expression and Transactivation

Cyclin D1 Repression of Peroxisome Proliferator-Activated Receptor γ Expression and Transactivation

Dehydroepiandrosterone Suppresses Elevated Hepatic Glucose-6-phosphatase mRNA Level in C57BL/KsJ-db/db Mice. Comparison with Troglitazone.

Identification of a Co-repressor That Inhibits the Transcriptional and Growth-Arrest Activities of CCAAT/Enhancer-binding Protein α

Contact Info

Product

Resources

About