A Peroxisome Proliferator-Activated Receptor γ-Retinoid X Receptor Heterodimer Physically Interacts with the Transcriptional Activator PAX6 to Inhibit Glucagon Gene Transcription

@article{Kratzner2008APP,
  title={A Peroxisome Proliferator-Activated Receptor $\gamma$-Retinoid X Receptor Heterodimer Physically Interacts with the Transcriptional Activator PAX6 to Inhibit Glucagon Gene Transcription},
  author={Ralph Krätzner and Florian Fr{\"o}hlich and Katrin Lepler and M. Schr{\"o}der and Katharina R{\"o}her and Corinna Dickel and Mladen Vassilev Tzvetkov and Thomas Quentin and Elke Oetjen and Willhart Knepel},
  journal={Molecular Pharmacology},
  year={2008},
  volume={73},
  pages={509 - 517}
}
The peptide hormone glucagon stimulates hepatic glucose output, and its levels in the blood are elevated in type 2 diabetes mellitus. The nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) has essential roles in glucose homeostasis, and thiazolidinedione PPARγ agonists are clinically important antidiabetic drugs. As part of their antidiabetic effect, thiazolidinediones such as rosiglitazone have been shown to inhibit glucagon gene transcription through binding to PPARγ and… 

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References

SHOWING 1-10 OF 51 REFERENCES
Repression of Glucagon Gene Transcription by Peroxisome Proliferator-activated Receptor γ through Inhibition of Pax6 Transcriptional Activity*
TLDR
Pax6 is defined as a novel functional target of PPARγ and inhibition of glucagon gene expression may be among the multiple mechanisms through which thiazolidinediones improve glycemic control in diabetic subjects.
The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation
TLDR
It is shown that PPAR-γ is markedly upregulated in activated macrophages and inhibits the expression of the inducible nitric oxide synthase, gelatinase B and scavenger receptor A genes in response to 15d-PGJ2 and synthetic PPar-γ ligands, suggesting that PPARS and locally produced prostaglandin D2 metabolites are involved in the regulation of inflammatory responses.
Peroxisome proliferator-activated receptor-gamma and retinoic acid X receptor alpha represses the TGFbeta1 gene via PTEN-mediated p70 ribosomal S6 kinase-1 inhibition: role for Zf9 dephosphorylation.
TLDR
Data indicate that activation of PPARgamma-RXR heterodimer represses the TGFbeta1 gene and induces Zf9 dephosphorylation via PTEN-mediated S6K1 inhibition, providing insight into pharmacological manipulation of the T GF beta1 gene regulation.
Peroxisome Proliferator-Activated Receptor-γ and Retinoic Acid X Receptor α Represses the TGFβ1 Gene via PTEN-Mediated p70 Ribosomal S6 Kinase-1 Inhibition: Role for Zf9 Dephosphorylation
TLDR
Data indicate that activation of PPARγ-RXR heterodimer represses the TGFβ1 gene and induces Zf9 dephosphorylation via PTEN-mediated S6K1 inhibition, providing insight into pharmacological manipulation of the T GF β1 gene regulation.
Peroxisomal proliferator-activated receptor-gamma upregulates glucokinase gene expression in beta-cells.
TLDR
It is concluded that PPAR-gamma regulates gene expression of glucose-sensing apparatus and thereby improves glucose-Sensing ability ofbeta-cells, contributing to the restoration of beta-cell function in type 2 diabetic subjects by troglitazone.
Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in normal human pancreatic islet cells.
TLDR
The hypothesis of a direct influence of peroxisome proliferator-activated receptor gamma agonist on human pancreatic endocrine cells is supported, both at the mRNA and protein levels.
Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ
TLDR
A general mechanism for the assembly of nuclear receptors with co-activators is suggested, based on the observation that two consecutive LXXLL motifs of SRC-1 make identical contacts with both subunits of a PPAR-γ homodimer.
Identification of ARA70 as a Ligand-enhanced Coactivator for the Peroxisome Proliferator-activated Receptor γ*
TLDR
It is shown that ARA70 can function as a ligand-enhanced coactivator of PPARγ, which suggests that cross-talk may occur betweenPPARγ- and AR-mediated responses in adipocytes.
Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists
TLDR
The data suggest that the RXR:PPARγ heterodimer is a single-function complex serving as a molecular target for treatment of insulin resistance, and may provide a new and effective treatment for NIDDM.
Targeted Elimination of Peroxisome Proliferator-Activated Receptor γ in β Cells Leads to Abnormalities in Islet Mass without Compromising Glucose Homeostasis
TLDR
It is shown that activation of PPARγ is sufficient to reduce the proliferation of cultured insulinoma cell lines and indicates that the mechanisms controlling β-cell hyperplasia in obesity are different from those that regulate baseline cell mass in the islet.
...
...