HGNC Approved Gene Symbol: CTBP1
Cytogenetic location: 4p16.3 Genomic coordinates (GRCh38): 4:1,211,445-1,250,355 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p16.3 | Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome | 617915 | Autosomal dominant | 3 |
The CTBP1 gene encodes a transcriptional regulator that interacts with chromatin-modifying enzymes to modulate gene expression in multiple cellular pathways. CTBP1 is thought to function mainly in transcriptional repression through recruitment of histone-modifying enzymes such as histone deacetylases and methyltransferases (summary by Beck et al., 2016).
The E1a region of group C adenoviruses encodes 2 nearly identical proteins that are largely responsible for the oncogenic properties of adenoviruses. Whereas the N-terminal half of these E1A proteins is sufficient for transformation, the C-terminal half appears to modulate transformation, tumorigenesis, and metastasis negatively. Boyd et al. (1993) purified a HeLa cell protein, designated CTBP1, that specifically binds to the C-terminal half of E1A proteins. CTBP1 is a phosphoprotein that migrates as a 48-kD doublet by SDS-PAGE. Katsanis and Fisher (1998) suggested that the doublet consists of CTBP1 and the closely related CTBP2 (602619).
Schaeper et al. (1995) independently isolated a CTBP1 cDNA from a B-cell library. The predicted 439-amino acid sequence contains the sequences of 2 peptides prepared from purified CTBP1. The authors coimmunoprecipitated CTPB1 and an E1A protein from extracts of mammalian cells that were expressing both proteins.
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 2-hybrid and direct binding assays, they concluded that CtBP1 binds to the short medial portion of delta-EF1 containing the PLDLSL motif. In cotransfection experiments, they observed that CtBP1 enhanced the transrepression activity of delta-EF1. Using Northern blot analysis and in situ hybridization with mouse embryos, Furusawa et al. (1999) detected CtBP1 expression throughout developmental stages and in a wide range of adult tissues. CtBP1 and CtBP2 expression correlates with delta-EF1 expression. The authors hypothesized that CtBP1 and CtBP2 function as corepressors of delta-EF1 action.
By PCR of a radiation hybrid panel, Katsanis and Fisher (1998) mapped the CTBP1 gene to chromosome 4p16.
Polycomb (Pc) is part of a Pc group (PcG) protein complex that is involved in repression of gene activity during Drosophila and vertebrate development. Using a yeast 2-hybrid assay, Sewalt et al. (1999) found that Xenopus Ctbp1 interacts with Xenopus Pc and that human CTBP2 interacts with PC2 (603079), a human Pc homolog. Immunofluorescence studies indicated that CTBP1 and CTBP2 partially colocalize with PC2 in large PcG domains in interphase nuclei. 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 PC2-mediated repression of gene expression involves an association with corepressors such as the CTBPs. 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. Northern blot analysis revealed that the CTBP1 gene was expressed as a 2.4-kb mRNA in all human tissues tested.
Pc2 recruits the transcriptional corepressor CTBP to PcG bodies. Kagey et al. (2003) showed that CTBP is sumoylated at a single lysine. In vitro, CTBP sumoylation minimally required the SUMO E1 and E2 (UBC9; 601661) and SUMO1 (601912). However, Pc2 dramatically enhanced CTBP sumoylation. The authors proposed that, in vivo, this is likely due to the ability of Pc2 to recruit both CTBP and UBC9 to PcG bodies, thereby bringing together substrate and E2 and stimulating the transfer of SUMO to CTBP. These results demonstrated that Pc2 is a SUMO E3 and suggested that PcG bodies may be sumoylation centers.
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.
Kumar et al. (2002) reported biochemical and crystallographic studies that revealed that CTBP1 is a functional dehydrogenase. In addition, both a cofactor-dependent conformational change, with NAD+ and NADH being equivalently effective, and the active site residues were linked to the binding of the PXDLS consensus recognition motif on repressors, such as E1A and RIP140 (602490). They concluded that CTBP1 is an NAD(+)-regulated component of critical complexes for specific repression events in cells.
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.
By yeast 3-hybrid analysis, Zhang et al. (2003) found that mouse Hipk2 (606868) interacted with an E1A-Ctbp complex. Expression of Hipk2 or exposure to ultraviolet (UV) irradiation reduced Ctbp levels via a proteasome-mediated pathway. Coexpression of kinase-inactive Hipk2 or small interfering RNA-mediated reduction in Hipk2 levels prevented the UV effect. Mutation of Ctbp ser422 prevented phosphorylation as well as UV- and Hipk2-directed Ctbp clearance. Deletion of Ctbp or reduction in Ctbp levels promoted apoptosis in p53 (191170)-deficient cells.
Gallop et al. (2005) found that the lysophosphatidic acid acyltransferase, or LPAAT, activity associated with CtBP/BARS (e.g., Weigert et al., 1999) is a copurification artifact.
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.
Deng et al. (2011) identified microRNA-137 (MIR137; 614304) as a regulator of CTBP1 expression. Expression of MIR137 was inversely correlated with that of CTBP1 in melanoma cell lines. The MIR137-binding site in the 3-prime UTR of CTBP1 mRNA is conserved from human to chicken. Pull-down assays revealed that MIR137 interacted with ARGO2 (EIF2C2; 606229) and CTBP1 mRNA. Cotransfection of MIR137 inhibited expression of a reporter gene containing the CTBP1 3-prime UTR, but not when the MIR137-binding site was deleted from the CTBP1 3-prime UTR. Western blot and quantitative RT-PCR analyses showed that MIR137 expression in a melanoma cell line reduced CTBP1 protein levels and increased expression of the CTBP1 target genes E-cadherin and BAX (600040).
In 4 unrelated patients with hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (HADDTS; 617915), Beck et al. (2016) identified a de novo heterozygous missense mutation in the CTBP1 gene (R331W; 602618.0001). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. One patient was maternally somatic mosaic for the mutation; his mother, who carried a low mutation load (5.3%), had no neurologic features. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated a dominant-negative effect. The patients were part of a cohort of 5,471 trios containing probands with neurodevelopmental disorders who underwent whole-exome sequencing.
In 4 unrelated patients with hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (HADDTS; 617915), Beck et al. (2016) identified a de novo heterozygous c.991C-T transition in the CTBP1 gene, resulting in an arg331-to-trp (R331W) substitution at a highly conserved residue in the PLDLS domain in the C-terminal region, which plays a role in the scaffolding function of CTBP1. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The R331W variant was not found in the dbSNP or ExAC databases, or in a local database of 24,578 exomes. One of the patients was maternally somatic mosaic for the mutation; his mother, who carried a low mutation load (5.3%), had no neurologic features. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated a dominant-negative effect.
Beck, D. B., Cho, M. T., Millan, F., Yates, C., Hannibal, M., O'Connor, B., Shinawi, M., Connolly, A. M., Waggoner, D., Halbach, S., Angle, B., Sanders, V., Shen, Y., Retterer, K., Begtrup, A., Bai, R., Chung, W. K. A recurrent de novo CTBP1 mutation is associated with developmental delay, hypotonia, ataxia, and tooth enamel defects. Neurogenetics 17: 173-178, 2016. [PubMed: 27094857] [Full Text: https://doi.org/10.1007/s10048-016-0482-4]
Boyd, J. M., Subramanian, T., Schaeper, U., La Regina, M., Bayley, S., Chinnadurai, G. A region in the C-terminus of adenovirus 2/5 E1a protein is required for association with a cellular phosphoprotein and important for the negative modulation of T24-ras mediated transformation, tumorigenesis and metastasis. EMBO J. 12: 469-478, 1993. [PubMed: 8440238] [Full Text: https://doi.org/10.1002/j.1460-2075.1993.tb05679.x]
Deng, Y., Deng, H., Bi, F., Liu, J., Bemis, L. T., Norris, D., Wang, X.-J., Zhang, Q. MicroRNA-137 targets carboxyl-terminal binding protein 1 in melanoma cell lines. Int. J. Biol. Sci. 7: 133-137, 2011. [PubMed: 21278922] [Full Text: https://doi.org/10.7150/ijbs.7.133]
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]
Gallop, J. L., Butler, P. J. G., McMahon, H. T. Endophilin and CtBP/BARS are not acyl transferases in endocytosis or Golgi fission. Nature 438: 675-678, 2005. [PubMed: 16319893] [Full Text: https://doi.org/10.1038/nature04136]
Kagey, M. H., Melhuish, T. A., Wotton, D. The polycomb protein Pc2 is a SUMO E3. Cell 113: 127-137, 2003. [PubMed: 12679040] [Full Text: https://doi.org/10.1016/s0092-8674(03)00159-4]
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]
Kumar, V., Carlson, J. E. Ohgi, K. A., Edwards, T. A., Rose, D. W., Escalante, C. R., Rosenfeld, M. G., Aggarwal, A. K. Transcription corepressor CtBP is an NAD(+)-regulated dehydrogenase. Molec. Cell 10: 857-869, 2002. [PubMed: 12419229] [Full Text: https://doi.org/10.1016/s1097-2765(02)00650-0]
Schaeper, U., Boyd, J. M., Verma, S., Uhlmann, E., Subramanian, T., Chinnadurai, G. Molecular cloning and characterization of a cellular phosphoprotein that interacts with a conserved C-terminal domain of adenovirus E1A involved in negative modulation of oncogenic transformation. Proc. Nat. Acad. Sci. 92: 10467-10471, 1995. Note: Erratum: Proc. Nat. Acad. Sci. 95: 14584 only, 1998. [PubMed: 7479821] [Full Text: https://doi.org/10.1073/pnas.92.23.10467]
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]
Weigert, R., Silletta, M. G., Spano, S., Turacchio, G., Cericola, C., Colanzi, A., Senatore, S., Mancini, R., Polishchuk, E. V., Salmona, M., Facchiano, F., Burger, K. N. J., Mironov, A., Luini, A., Corda, D. CtBP/BARS induces fission of Golgi membranes by acylating lysophosphatidic acid. Nature 402: 429-433, 1999. [PubMed: 10586885] [Full Text: https://doi.org/10.1038/46587]
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]
Zhang, Q., Yoshimatsu, Y., Hildebrand, J., Frisch, S. M., Goodman, R. H. Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP. Cell 115: 177-186, 2003. [PubMed: 14567915] [Full Text: https://doi.org/10.1016/s0092-8674(03)00802-x]