HGNC Approved Gene Symbol: GPS2
Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38): 17:7,312,661-7,315,360 (from NCBI)
GPS2 is a physiologic coregulator of cholesterol homeostasis that affects cholesterol to bile acid biosynthesis in liver and participates in cholesterol transport and efflux in macrophages via activation of ABCG1 (603076) (Sanyal et al., 2007; Jakobsson et al., 2009).
Spain et al. (1996) used a yeast complementation system to identify proteins involved in G protein-mitogen-activated protein kinase (MAPK) signaling cascades. They cloned the genes of 2 such proteins, GPS1 (601934) and GPS2. Sequence analysis revealed that the GPS2 gene encodes a 327-amino acid polypeptide.
Spain et al. (1996) found that, when overexpressed in mammalian cells, GPS1 or GPS2 could potently suppress a RAS (190020)- and MAPK-mediated signal and interfere with JNK (601158) activity, suggesting that the function of these genes may be signal repression.
Zhang et al. (2002) reported that GPS2, a protein involved in intracellular signaling, is an integral subunit of the NCOR1 (600849)-HDAC3 (605166) complex. They determined structural motifs that direct the formation of a highly stable and active deacetylase complex. GPS2 and TBL1 (300196), another component of the NCOR1-HDAC3 complex, interact cooperatively with repression domain-1 of NCOR1 to form a heterotrimeric structure and are indirectly linked to HDAC3 via an extended NCOR1 SANT domain that also activates latent HDAC3 activity. Zhang et al. (2002) also showed that the NCOR1-HDAC3 complex inhibits JNK activation through the associated GPS2 subunit and thus could potentially provide an alternative mechanism for hormone-mediated antagonism of AP1 (165160) function.
Sanyal et al. (2007) presented evidence that the NCOR1 subunit GPS2 regulates expression of CYP7A1 (118455) and CYP8B1 (602172), 2 major enzymes involved in bile acid biosynthesis in liver.
Jakobsson et al. (2009) identified GPS2 as a coregulator required for expression of the cholesterol transporter ABCG1 and the resultant cholesterol efflux in human hepatic and macrophage cell lines and in primary human hepatocytes. In macrophages, silencing of GPS2 by RNA interference reduced ABCG1 expression and diminished ABCG1-mediated cholesterol efflux. Upon activation of LXR (see NR1H3; 602423) by its ligand, GPS2 facilitated LXR recruitment to an ABCG1 promoter/enhancer unit, followed by histone H3 (see 602810) lys9 demethylation. Chromatin immunoprecipitation analysis and 2-hybrid and protein-protein interactions assays revealed that GPS2 interacted with the LXR-RXR (see RXRA; 180245) heterodimer at the LXR element of the ABCG1 promoter. GPS2 also appeared to stabilize the intrachromosomal association of the ABCG1 promoter with an enhancer element separated from the promoter region by over 35 kb. In contrast with its role at the ABCG1 promoter, GPS2 behaved as a corepressor at the ABCA1 (600046) promoter. GPS2 occupied the ABCA1 promoter in a corepressor complex in the absence of ligand and was released from the ABCA1 promoter upon LXR activation.
Jakobsson, T., Venteclef, N., Toresson, G., Damdimopoulos, A. E., Ehrlund, A., Lou, X., Sanyal, S., Steffensen, K. R., Gustafsson, J.-A., Treuter, E. GPS2 is required for cholesterol efflux by triggering histone demethylation, LXR recruitment, and coregulator assembly at the ABCG1 locus. Molec. Cell 34: 510-518, 2009. [PubMed: 19481530] [Full Text: https://doi.org/10.1016/j.molcel.2009.05.006]
Sanyal, S., Bavner, A., Haroniti, A., Nilsson, L.-M., Lundasen, T., Rehnmark, S., Witt, M. R., Einarsson, C., Talianidis, I., Gustafsson, J.-A., Treuter, E. Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis. Proc. Nat. Acad. Sci. 104: 15665-15670, 2007. [PubMed: 17895379] [Full Text: https://doi.org/10.1073/pnas.0706736104]
Spain, B. H., Bowdish, K. S., Pacal, A. R., Staub, S. F., Koo, D., Chang, K.-Y. R., Xie, W., Colicelli. Two human cDNAs, including a homolog of Arabidopsis FUS6 (COP11), suppress G-protein- and mitogen-activated protein kinase-mediated signal transduction in yeast and mammalian cells. Molec. Cell. Biol. 16: 6698-6706, 1996. [PubMed: 8943324] [Full Text: https://doi.org/10.1128/MCB.16.12.6698]
Zhang, J., Kalkum, M., Chait, B. T., Roeder, R. G. The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2. Molec. Cell 9: 611-623, 2002. [PubMed: 11931768] [Full Text: https://doi.org/10.1016/s1097-2765(02)00468-9]