Reactome | Corepressors are released from liganded PPARG:RXRA heterodimer

Corepressors are released from liganded PPARG:RXRA heterodimer

Stable Identifier

R-HSA-9843117

Type

Reaction [transition]

Species

Homo sapiens

Compartment

nucleoplasm

ReviewStatus

5/5

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Gene expression (Transcription) (Homo sapiens)

- Epigenetic regulation of gene expression (Homo sapiens)
  - Epigenetic regulation by WDR5-containing histone modifying complexes (Homo sapiens)
    - Epigenetic regulation of gene expression by MLL3 and MLL4 complexes (Homo sapiens)
      - Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes (Homo sapiens)
        
        MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis (Homo sapiens)
        
        Corepressors are released from liganded PPARG:RXRA heterodimer (Homo sapiens)

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Corepressors are released from liganded PPARG:RXRA heterodimer

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Binding of activator ligands to the PPARG:RXRA dimer causes loss of the NCoR/SMRT corepressor complexes from target gene promoters (reviewed in Farmer 2006, Cohen 2006, Jeninga et al. 2009). Based on ChIP analysis in mouse adipocytes, NCoR/SMRT components NCOR1 (NCoR), NCOR2 (SMRT), and HDAC3 show decreased association with PPARG target genes in the presence of PPARG agonists (Guan et al. 2005). Dominant-negative germline PPARG variants PPARG1 P467L (PPARG2 P495L) and PPARG1 V290M (PPARG2 V318M), responsible for partial lipodystrophy with severe insulin resistance, destabilize PPARG tertiary structure to favor receptor-corepressor interaction, and were shown to impair dissociation of NCOR2 (SMRT) from PPARG in the presence of PPARG agonists and result in repression of PPARG target genes (Agostini et al. 2004). Recombinant human NCOR1 and NCOR2 were shown to be released from recombinant human PPARG2 in the presence of PPARG agonists (Fujimura et al. 2005). Based on in vitro experiments using recombinant human PPARG:RXRA complex associated with oligonucleotides that contain peroxisome proliferator response element (PPRE) and recombinant mouse Ncor1 or Ncor2, addition of PPARG agonists causes dissociation of Ncor1 and Ncor2 (Gurnell et al. 2000). The interaction between human PPARG2 and NCOR1 is abolished in the presence of PPARG agonists (Oberfield et al. 1999, Xi et al. 2015). Proteins TBL1X (TBL1) and TBL1XR1 (TBLR1), components of the NCoR/SMRT complexes, were reported to be required for transactivation of PPARG target genes upon ligand-mediated activation of PPARG by recruitment of the 19S proteasome and subsequent proteasome-mediated degradation of NCoR/SMRT subunits NCOR1, NCOR2, and HDAC3, which facilitates the release of corepressors from DNA-bound PPARG:RXRA dimers (Perissi et al. 2004). Based on mammalian two-hybrid assay using recombinant mouse proteins, Ncor1 and Ncor2 binding to Pparg is reduced in the presence of Pparg agonists (Allen et al. 2006).

Literature References

PubMed ID	Title	Journal	Year
16314690	FK614, a novel peroxisome proliferator-activated receptor gamma modulator, induces differential transactivation through a unique ligand-specific interaction with transcriptional coactivators Fujimura, T, Sakuma, H, Konishi, S, Oe, T, Hosogai, N, Kimura, C, Aramori, I, Mutoh, S	J Pharmacol Sci	2005
14657011	Tyrosine agonists reverse the molecular defects associated with dominant-negative mutations in human peroxisome proliferator-activated receptor gamma Agostini, M, Gurnell, M, Savage, DB, Wood, EM, Smith, AG, Rajanayagam, O, Garnes, KT, Levinson, SH, Xu, HE, Schwabe, JW, Willson, TM, O'Rahilly, S, Chatterjee, VK	Endocrinology	2004
25305559	L312, a novel PPARγ ligand with potent anti-diabetic activity by selective regulation Xie, X, Zhou, X, Chen, W, Long, L, Li, W, Yang, X, Li, S, Wang, L	Biochim Biophys Acta	2015