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PPAR-gamma Signaling Crosstalk in Mesenchymal Stem Cells.

Takada I, Kouzmenko AP, Kato S - PPAR Res (2010)

Bottom Line: Since several cytokines (IL-1, TNF-alpha, TGF-beta) had been known to inhibit adipocyte differentiation in mesenchymal stem cells (MSCs), we examined the effect of these cytokines on the transactivation function of PPAR-gamma.This resulted in histoneH3K9 tri-methylation at PPAR-gamma target gene promoters.Overall, our data show that cytokines and noncanonical Wnts play a crucial role in modulation of PPAR-gamma regulatory function in its target cells and tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.

ABSTRACT
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor (NR) superfamily of ligand-activated transcriptional factors. Among other functions, PPAR-gamma acts as a key regulator of the adipogenesis. Since several cytokines (IL-1, TNF-alpha, TGF-beta) had been known to inhibit adipocyte differentiation in mesenchymal stem cells (MSCs), we examined the effect of these cytokines on the transactivation function of PPAR-gamma. We found that the TNF-alpha/IL-1-activated TAK1/TAB1/NIK (NFkappaB-inducible kinase) signaling cascade inhibited both the adipogenesis and Tro-induced transactivation by PPAR-gamma by blocking the receptor binding to the cognate DNA response elements. Furthermore, it has been shown that the noncanonical Wnts are expressed in MSCs and that Wnt-5a was capable to inhibit transactivation by PPAR-gamma. Treatment with Wnt5a-activated NLK (nemo-like kinase) induced physical association of the endogenous NLK and H3K9 histone methyltransferase (SETDB1) protein complexes with PPAR-gamma. This resulted in histoneH3K9 tri-methylation at PPAR-gamma target gene promoters. Overall, our data show that cytokines and noncanonical Wnts play a crucial role in modulation of PPAR-gamma regulatory function in its target cells and tissues.

No MeSH data available.


Related in: MedlinePlus

Schema of the proposed molecular mechanism of adipogenesis inhibition by TNF-α and IL-1 through suppression of PPAR-γ function by NF-κB activated via the NIK-TAK1/TAB1-mediated cascade.
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Related In: Results  -  Collection


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fig2: Schema of the proposed molecular mechanism of adipogenesis inhibition by TNF-α and IL-1 through suppression of PPAR-γ function by NF-κB activated via the NIK-TAK1/TAB1-mediated cascade.

Mentions: Consistent with suppression of the PPAR-γ-dependent luciferase reporter gene activity, the activated TAK1/TAB1/NIK was found to suppress the Tro-induced expression of endogenous PPAR-γ target genes. We found that treatment with these cytokines or ectopic expression of some of their downstream mediators blocked binding of PPAR-γ to its response element DNA sequences (PPRE) in the target gene promoters (Cbl-associated protein, CAP). CAP is a signaling protein that interacts with both c-Cbl and the insulin receptor that may be involved in the specific insulin-stimulated tyrosine phosphorylation of c-Cbl [25, 26]. Next, we have shown that the TAK1/TAB1/NIK pathway-activated NF-κB blocks the DNA binding of PPAR-γ at the PPRE. Together with the previous reports that agonist-activated PPAR-γ inhibits DNA binding by NF-κB [27], it appears that an association of ligand-activated PPAR-γ with nuclear NF-κB results in a complex incapable to interact with DNA at either corresponding binding sites (Figure 2).


PPAR-gamma Signaling Crosstalk in Mesenchymal Stem Cells.

Takada I, Kouzmenko AP, Kato S - PPAR Res (2010)

Schema of the proposed molecular mechanism of adipogenesis inhibition by TNF-α and IL-1 through suppression of PPAR-γ function by NF-κB activated via the NIK-TAK1/TAB1-mediated cascade.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2913631&req=5

fig2: Schema of the proposed molecular mechanism of adipogenesis inhibition by TNF-α and IL-1 through suppression of PPAR-γ function by NF-κB activated via the NIK-TAK1/TAB1-mediated cascade.
Mentions: Consistent with suppression of the PPAR-γ-dependent luciferase reporter gene activity, the activated TAK1/TAB1/NIK was found to suppress the Tro-induced expression of endogenous PPAR-γ target genes. We found that treatment with these cytokines or ectopic expression of some of their downstream mediators blocked binding of PPAR-γ to its response element DNA sequences (PPRE) in the target gene promoters (Cbl-associated protein, CAP). CAP is a signaling protein that interacts with both c-Cbl and the insulin receptor that may be involved in the specific insulin-stimulated tyrosine phosphorylation of c-Cbl [25, 26]. Next, we have shown that the TAK1/TAB1/NIK pathway-activated NF-κB blocks the DNA binding of PPAR-γ at the PPRE. Together with the previous reports that agonist-activated PPAR-γ inhibits DNA binding by NF-κB [27], it appears that an association of ligand-activated PPAR-γ with nuclear NF-κB results in a complex incapable to interact with DNA at either corresponding binding sites (Figure 2).

Bottom Line: Since several cytokines (IL-1, TNF-alpha, TGF-beta) had been known to inhibit adipocyte differentiation in mesenchymal stem cells (MSCs), we examined the effect of these cytokines on the transactivation function of PPAR-gamma.This resulted in histoneH3K9 tri-methylation at PPAR-gamma target gene promoters.Overall, our data show that cytokines and noncanonical Wnts play a crucial role in modulation of PPAR-gamma regulatory function in its target cells and tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.

ABSTRACT
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor (NR) superfamily of ligand-activated transcriptional factors. Among other functions, PPAR-gamma acts as a key regulator of the adipogenesis. Since several cytokines (IL-1, TNF-alpha, TGF-beta) had been known to inhibit adipocyte differentiation in mesenchymal stem cells (MSCs), we examined the effect of these cytokines on the transactivation function of PPAR-gamma. We found that the TNF-alpha/IL-1-activated TAK1/TAB1/NIK (NFkappaB-inducible kinase) signaling cascade inhibited both the adipogenesis and Tro-induced transactivation by PPAR-gamma by blocking the receptor binding to the cognate DNA response elements. Furthermore, it has been shown that the noncanonical Wnts are expressed in MSCs and that Wnt-5a was capable to inhibit transactivation by PPAR-gamma. Treatment with Wnt5a-activated NLK (nemo-like kinase) induced physical association of the endogenous NLK and H3K9 histone methyltransferase (SETDB1) protein complexes with PPAR-gamma. This resulted in histoneH3K9 tri-methylation at PPAR-gamma target gene promoters. Overall, our data show that cytokines and noncanonical Wnts play a crucial role in modulation of PPAR-gamma regulatory function in its target cells and tissues.

No MeSH data available.


Related in: MedlinePlus