HGNC Approved Gene Symbol: CTBP2
Cytogenetic location: 10q26.13 Genomic coordinates (GRCh38): 10:124,984,317-125,162,463 (from NCBI)
The E1a region of group C adenoviruses encodes 2 nearly identical proteins that are largely responsible for the oncogenic properties of adenoviruses. The CTBP1 (602618) protein binds to the C-terminal half of these E1A proteins. Katsanis and Fisher (1998) identified CTBP2 by searching for expressed sequence tags (ESTs) with homology to CTBP1. The predicted 445-amino acid CTBP2 protein is 72% identical to CTBP1. Northern blot analysis showed that the CTBP2 gene was expressed as a 3.8-kb mRNA in all tissues tested, with the most abundant expression in heart, skeletal muscle, and pancreas.
Furusawa et al. (1999) identified the mouse homologs of CTBP1 and CTBP2 in a yeast 2-hybrid screen for proteins that interact with delta-EF1 (TCF8; 189909), a transcriptional repressor that binds the E2-box (CACCTG) and related sequences. Using Northern blot analysis and in situ hybridization with mouse embryos, Furusawa et al. (1999) detected expression of 2 Ctbp2 transcripts confined to the embryonic stages. Ctbp1 and Ctbp2 expression correlated with delta-EF1 expression.
Schmitz et al. (2000) identified an alternate product of the CTBP2 locus, which they named RIBEYE. They cloned full-length cDNAs corresponding to RIBEYE in bovine, rat, and human. Human RIBEYE encodes a deduced protein of 985 amino acids. Based on sequence analysis, the authors defined a unique N-terminal A domain of RIBEYE and a C-terminal B domain identical to the previously identified CTBP2. They found that RIBEYE and CTBP2 are transcribed from distinct promoters of the CTBP2 gene. The unique N-terminal sequences of RIBEYE and CTBP2 are encoded by separate 5-prime exons, and the shared C-terminal sequences are encoded by 8 common 3-prime exons. By Northern blot analysis and immunoblotting, Schmitz et al. (2000) detected a 120-kD RIBEYE product expressed only in the retina, whereas the 50-kD CTBP2 product was observed ubiquitously in most tissues. Using immunocytochemistry, they demonstrated that RIBEYE is a specific component of synaptic ribbons in the retina and hypothesized that RIBEYE may be a general component of all synaptic ribbons. Using transfection experiments, Schmitz et al. (2000) demonstrated that the N-terminal A domain of RIBEYE can form protein aggregates. They hypothesized that the A domain may function in the formation of stable ribbon structures, whereas the B domain may be exposed on the surface of the ribbons. The B domain shares homology with 2-hydroxyacid dehydrogenases and binds to NAD+ with high affinity. They hypothesized that the B domain may serve as an enzyme in synaptic vesicle priming on synaptic ribbons and in transcriptional repression.
Using a yeast 2-hybrid assay and mutation analysis, Turner and Crossley (1998) found that mouse Ctbp2 interacted with the pro-val-asp-leu-thr motif in the repression domain of Bklf (KLF3; 609392). When tethered to a promoter by a heterologous DNA-binding domain, Ctbp2 functioned as a potent repressor. Ctbp2 also interacted with the mammalian transcription factors Evi1 (165215), Tcf8, and Fog (ZFPM1; 601950). Turner and Crossley (1998) concluded that CTBP2 is a mammalian corepressor that targets diverse transcriptional regulators.
Using 2-hybrid and direct binding assays, Furusawa et al. (1999) showed that Ctbp2 bound the short medial portion of delta-EF1 containing the PLDLSL motif. In cotransfection experiments, they observed that Ctbp2 enhanced transrepression activity of delta-EF1. The authors hypothesized that Ctbp1 and Ctbp2 function as corepressors of delta-EF1 action.
In Drosophila and in vertebrates, the Polycomb (Pc) group (PcG) genes have been identified as being part of a cellular memory system that is responsible for the stable and heritable repression of gene expression. PC2 (603079), a human Pc homolog, CBX2 (602770), HPH1 (602978), HPH2 (602979), BMI1 (164831), and RING1 (602045) form a complex that localizes in large nuclear domains termed PcG domains. Using a yeast 2-hybrid assay, Sewalt et al. (1999) found that CTBP2 interacts with PC2 and that Xenopus Ctbp1 interacts with Xenopus Pc. The CTBP2 and PC2 interaction also exists in vivo, since the proteins coimmunoprecipitate with each other and partially colocalize in large PcG domains in interphase nuclei. CTBP1 showed the same localization pattern. As with PC2, chimeric LexA-CTBP2 and LexA-CTBP1 proteins repressed gene activity when targeted to a reporter gene. Sewalt et al. (1999) suggested that the CTBP proteins target PC2, and thereby the PcG complex, to particular loci in chromatin that contain binding sites for specific repressors of gene activity, thereby forming a complex between the repressors and the PcG complex, with CTBP as a bridging protein. They speculated that the interference of the adenoviral E1A protein with the transcription machinery of the infected cell may involve interference with PcG-mediated repression through disruption of the CTBP-PcG interaction.
Zhang et al. (2002) demonstrated that CTBP binding to cellular and viral transcriptional repressors is regulated by NAD+ and NADH, with NADH being 2 to 3 orders of magnitude more effective. Levels of free nuclear nicotinamide adenine dinucleotides, determined using 2-photon microscopy, corresponded to the levels required for half-maximal CTBP binding and were considerably lower than those previously reported. Agents capable of increasing NADH levels stimulated CTBP binding to its partners in vivo and potentiated CTBP-mediated repression. Zhang et al. (2002) proposed that this ability to detect changes in nuclear NAD+/NADH ratio allows CTBP to serve as a redox sensor for transcription.
CTBP is recruited to DNA by transcription factors that contain a PXDLS motif. Shi et al. (2003) reported the identification of a CTBP complex that contains the essential components for both gene targeting and coordinated histone modifications, allowing for the effective repression of genes targeted by CTBP. This complex has a molecular mass of about 1.3 to 1.5 million and contains CTBP1 and CTBP2 as well as G9A (604599), EUHMT (607001), COREST (607675), HDAC1 (601241) and HDAC2 (605164), NPAO, REBB1, ZNF217 (602967), and KIAA0222. Immunoprecipitation with G9A antibodies brought down the same components as well as HPC2 (ELAC2; 605367). Shi et al. (2003) found that inhibiting the expression of CTBP and its associated histone-modifying activities by RNA-interference resulted in alterations of histone modifications at the promoter of the tumor invasion suppressor gene E-cadherin (192090) and increased promoter activity in a reporter assay.
Using a promoter pull-down assay followed by mass spectrometry analysis, Flajollet et al. (2009) identified RREB1 (602209) as a protein that bound the HLA-G (142871) promoter. RREB1 exerted repressive activity on the promoter in HLA-G-negative cells that was mediated by recruitment of HDAC1 and CTBP1 and/or CTBP2. The HLA-G promoter contains 3 RREB1 target sites. Flajollet et al. (2009) proposed that the repressive activity of RREB1 on the HLA-G promoter may be regulated by posttranslational modifications governing its association with CTBP.
Thomas et al. (2008) identified the CTBP2 gene on chromosome 10q26.13, within a region associated with susceptibility to prostate cancer (176807).
Flajollet, S., Poras, I., Carosella, E. D., Moreau, P. RREB-1 is a transcriptional repressor of HLA-G. J. Immun. 183: 6948-6959, 2009. [PubMed: 19890057] [Full Text: https://doi.org/10.4049/jimmunol.0902053]
Furusawa, T., Moribe, H., Kondoh, H., Higashi, Y. Identification of CtBP1 and CtBP2 as corepressors of zinc finger-homeodomain factor delta-EF1. Molec. Cell. Biol. 19: 8581-8590, 1999. [PubMed: 10567582] [Full Text: https://doi.org/10.1128/MCB.19.12.8581]
Katsanis, N., Fisher, E. M. C. A novel C-terminal binding protein (CTBP2) is closely related to CTBP1, an adenovirus E1A-binding protein, and maps to human chromosome 21q21.3. Genomics 47: 294-299, 1998. [PubMed: 9479502] [Full Text: https://doi.org/10.1006/geno.1997.5115]
Schmitz, F., Konigstorfer, A., Sudhof, T. C. RIBEYE, a component of synaptic ribbons: a protein's journey through evolution provides insight into synaptic ribbon function. Neuron 28: 857-872, 2000. [PubMed: 11163272] [Full Text: https://doi.org/10.1016/s0896-6273(00)00159-8]
Sewalt, R. G. A. B., Gunster, M. J., van der Vlag, J., Satijn, D. P. E., Otte, A. P. C-terminal binding protein is a transcriptional repressor that interacts with a specific class of vertebrate polycomb proteins. Molec. Cell. Biol. 19: 777-787, 1999. [PubMed: 9858600] [Full Text: https://doi.org/10.1128/MCB.19.1.777]
Shi, Y., Sawada, J., Sui, G., Affar, E. B., Whetstine, J. R., Lan, F., Ogawa, H., Luke, M. P.-S., Nakatani, Y., Shi, Y. Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature 422: 735-738, 2003. [PubMed: 12700765] [Full Text: https://doi.org/10.1038/nature01550]
Thomas, G., Jacobs, K. B., Yeager, M., Kraft, P., Wacholder, S., Orr, N., Yu, K., Chatterjee, N., Welch, R., Hutchinson, A., Crenshaw, A., Cancel-Tassin, G., and 27 others. Multiple loci identified in a genome-wide association study of prostate cancer. Nature Genet. 40: 310-315, 2008. [PubMed: 18264096] [Full Text: https://doi.org/10.1038/ng.91]
Turner, J., Crossley, M. Cloning and characterization of mCtBP2, a co-repressor that associates with basic Kruppel-like factor and other mammalian transcriptional regulators. EMBO J. 17: 5129-5140, 1998. [PubMed: 9724649] [Full Text: https://doi.org/10.1093/emboj/17.17.5129]
Zhang, Q., Piston, D. W., Goodman, R. H. Regulation of corepressor function by nuclear NADH. Science 295: 1895-1897, 2002. [PubMed: 11847309] [Full Text: https://doi.org/10.1126/science.1069300]