G-protein pathway suppressor 2 (GPS2) was identified as a co-regulator required for NR1H2, NR1H3-induced transcription of the ABCG1 gene in human hepatic HepG2 and macrophage THP-1 cells (Jakobsson T et al. 2009).", "cellular_location": "plasma membrane", "input_participant_list": [ "R-HSA-9024355" ], "output_participant_list": [ "R-HSA-2975951" ], "enzyme_list": [ "Q9Y4C1-1", "Q8NB78-1", "P45844-1", "O60341-1", "O75164-1" ], "evidence": [ { "id": "R-HSA-9024361", "database": "Reactome", "url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9024361" } ] }, { "id": "R-HSA-9024386", "name": "Oxysterol-induced binding of NR1H2,3:RXR to the ABCG1 gene", "equation": "", "summary": "The ATP binding cassette transporter G1 (ABCG1, formerly called \u201cwhite\u201d and/or ABC8) exhibits a tissue-specific expression pattern with high expression levels found in macrophage/microglia, lung, brain, spleen, adrenal gland, heart and liver (Croop JM et al 1997; Klucken J et al. 2000). The ABCG1 gene is transcriptionally activated by cholesterol-loading and agonists of liver X receptors (LXR\u03b1/NR1H3 and LXR\u03b2/NR1H2) and retinoid X receptors (RXRs) and has been implicated in the efflux of cholesterol to high density lipoprotein (HDL) (Venkateswaran A et al. 2000; Kennedy MA et al. 2001; Ayaori M et al. 2012; Sabol SL et al. 2005; Jakobsson T et al. 2009). Beyond a role in cellular lipid homeostasis, ABCG1 participates in glucose and lipid metabolism by controlling the secretion and activity of insulin and lipoprotein lipase (Olivier M et al. 2012; Sturek JM et al. 2010; Hardy LM et al. 2017). ABCG1 gene has been mapped to chromosome 21q22.3 and multiple human ABCG1 transcripts have been detected resulting from different transcription initiation and alternative mRNA splicing (Croop JM et al 1997; Langmann T et al. 2000; Lorkowski S et al. 2001; Kennedy MA et al. 2001). Although discrepancies were initially found among reports in the literature regarding the structure of the ABCG1 gene, it is now established that the ABCG1 gene is composed of 23 exons encoding a protein that forms a half transporter with 6 transmembrane spanning domains and a single intracellular nucleotide binding domain (NBD) (Langmann T et al. 2000; Kennedy MA et al. 2001; Hardy LM et al. 2017). This NBD domain contains highly conserved Walker A and Walker B motifs and is required for the binding and the hydrolysis of ATP which might provide required energy to transport substrates across the membrane (Cserepes J et al. 2004; Hirayama H et al. 2013; Vaughan AM & Oram JF 2005). Induction of ABCG1 expression by LXR agonists likely involves the presence of multiple LXR response elements (LXRE) throughout the ABCG1 gene (Kennedy MA et al. 2001; Sabol SL et al. 2005; Uehara Y et al. 2007). Electromobility shift assays demonstrated that NR1H3 and RXR alpha bind to two LXREs in intron 7 (Kennedy MA et al. 2001). Another set of two functional LXREs, LXRE-A and LXRE-B, was identified in the first and second introns of the human ABCG1 gene (Sabol SL et al. 2005). Further, studies of the transcriptional activity of truncated human ABCG1 promoter constructs showed that the NR1H2,3:RXR response region (or LXRE) is located in the human ABCG1 promoter A (LXRE-A) between -303 and -233 (Uehara Y et al. 2007).
G-protein pathway suppressor 2 (GPS2) was identified as a co-regulator required for NR1H2,3-induced transcription of the ABCG1 gene in human hepatic HepG2 and macrophage THP-1 cells (Jakobsson T et al. 2009). In macrophages, silencing of GPS2 by RNA interference reduced ABCG1 expression and diminished ABCG1-mediated cholesterol efflux. Chromatin immunoprecipitation analysis and 2-hybrid and protein-protein interaction assays revealed that GPS2 interacted with NR1H2,3:RXR heterodimer at the LXRE of the ABCG1 promoter (Jakobsson T et al. 2009). Chromosome conformation capture assays using the human hepatoma cell line, Huh7, transfected with GPS2-targeting siRNAs showed that GPS2 was required for intrachromosomal communication of the ABCG1 promoter and enhancer triggered by NR1H2,3 activation (Jakobsson T et al. 2009). Further, ligand activation of NR1H2,3 induced two functionally coupled GPS2-dependent processes: (1) receptor recruitment to an ABCG1 promoter/enhancer unit and (2) lysine-specific histone demethylase 1 (KDM1)-dependent H3K9 demethylation (Jakobsson T et al. 2009). The model suggests that the H3K9 methylation imposes a chromatin barrier at certain genomic loci (e.g., ABCG1) that prevents nuclear receptors (NR) (e.g., NR1H2,3) from high-affinity DNA binding (as detected by ChIP assays). Ligand activation in vivo triggers recruitment of KDMs to NRs (in the case of NR1H2,3 via GPS2), thereby facilitating H3K9 demethylation and high-affinity DNA binding (Jakobsson T et al. 2009).",
"cellular_location": "nucleoplasm",
"input_participant_list": [],
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"Q9Y4C1-1",
"Q8NB78-1",
"O60341-1",
"O75164-1"
],
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"id": "R-HSA-9024386",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9024386"
}
]
},
{
"id": "R-HSA-9679787",
"name": "HDAC1:2-containing complex binds HDAC2 Inhibitors",
"equation": "",
"summary": "To carry out gene expression, a cell must control the winding and unwinding of DNA around histones. This is mediated by histone acetyl transferases (HATs) and histone deacetylases (HDACs). HDAC inhibitors inhibit the proliferation of tumour cells by inducing cell cycle arrest, differentiation and/or apoptosis (Zhang et al. 2019). Belinostat (Marks et al. 2000, O'Connor et al. 2015), vorinostat (Marks & Breslow 2007) and romidepsin (Ueda et al. 1994, VanderMolen et al. 2011) are HDAC inhibitors approved for the treatment of Peripheral T-cell lymphomas (PTCLs) (Hood & Shah 2016). These drugs are believed to bind to many, if not all HDAC proteins.
Human papillomaviruses (HPVs) cause epithelial proliferative diseases. The HDAC inhibitors vorinostat, belinostat and panobinostat have been shown to inhibit HPV DNA amplification and cause apoptosis in preclinical experiments (Banerjee et al. 2018).
The antiepileptic drug valproic acid inhibits HDAC2 and therefore is a promising drug for cancer therapy (G\u00f6ttlicher et al. 2001).",
"cellular_location": "nucleoplasm",
"input_participant_list": [],
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"O60341-1",
"Q13547-1",
"Q14839-1",
"Q12873-1",
"Q92769-1"
],
"evidence": [
{
"id": "R-HSA-9679787",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9679787"
}
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"id": "R-HSA-996727",
"name": "REST recruits the BHC complex",
"equation": "",
"summary": "The BHC (BRAF-HDAC) complex is involved in the repression of neuronal-specific genes during development. It is recruited by RE1-silencing transcription factor (REST) to mediate the repression of REST-responsive genes. The BHC complex includes histone deacetylases (HDACs) 1 and 2, and the histone demethylase KDM1A (also knowns as BHC110, LSD1 or AOF2). KDM1A demethylates both Lys-4 (H3K4me) and Lys-9 (H3K9me) of histone H3, acting as a coactivator or a corepressor, depending on the context. Corepressor for element-1-silencing transcription factor (CoREST) is an essential component of the BHC complex, enhancing the association with nucleosomes (Lee et al. 2005).
REST is a modular transcriptional regulator that recruits CoREST and other regulatory cofactors to activate or repress transcription through dynamic epigenetic mechanisms (Ballas & Mandel 2005).",
"cellular_location": "nucleoplasm",
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"Q13547-1",
"Q92769-1"
],
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{
"id": "R-HSA-996727",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-996727"
}
]
}
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