CTBP1

C-terminal-binding protein 1 also known as CtBP1 is a protein that in humans is encoded by the CTBP1 gene.^[5] CtBP1 is one of two CtBP proteins, the other protein being CtBP2.^[6]

CTBP1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1MX3, 4LCE, 4U6Q
Identifiers
Aliases	CTBP1, C-terminal binding protein 1, BARS, HADDTS
External IDs	OMIM: 602618; MGI: 1201685; HomoloGene: 1015; GeneCards: CTBP1; OMA:CTBP1 - orthologs
Gene location (Human) Chr. Chromosome 4 (human)[1] Band 4p16.3 Start 1,211,445 bp[1] End 1,249,953 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5 B1|5 17.52 cM Start 33,405,067 bp[2] End 33,432,338 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in tendon of biceps brachii right hemisphere of cerebellum internal globus pallidus anterior pituitary postcentral gyrus buccal mucosa cell body of pancreas Region I of hippocampus proper stromal cell of endometrium prefrontal cortex Top expressed in renal corpuscle medullary collecting duct ventricular zone tail of embryo fetal liver hematopoietic progenitor cell ganglionic eminence Rostral migratory stream Paneth cell dentate gyrus of hippocampal formation granule cell medial ganglionic eminence More reference expression data BioGPS More reference expression data
Gene ontology Molecular function oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor transcription corepressor activity protein domain specific binding DNA-binding transcription factor activity NAD binding transcription factor binding protein C-terminus binding protein binding oxidoreductase activity identical protein binding hydroxypyruvate reductase activity glyoxylate reductase (NADP+) activity protein homodimerization activity Cellular component cytoplasm transcription regulator complex transcription repressor complex nucleoplasm nucleus cytosol presynaptic active zone cytoplasmic component glutamatergic synapse GABA-ergic synapse Biological process positive regulation of histone deacetylation cell differentiation regulation of transcription, DNA-templated viral genome replication negative regulation of transcription by RNA polymerase II transcription, DNA-templated regulation of cell cycle negative regulation of histone H4 acetylation protein phosphorylation white fat cell differentiation metabolism viral process negative regulation of transcription, DNA-templated negative regulation of histone acetylation negative regulation of cell population proliferation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1487 13016 Ensembl ENSG00000159692 ENSMUSG00000037373 UniProt Q13363 O88712 RefSeq (mRNA) NM_001012614 NM_001328 NM_001377186 NM_001377187 NM_001377188 NM_001377189 NM_001377190 NM_001377191 NM_001377192 NM_001377193 NM_001198859 NM_001198860 NM_001198861 NM_013502 NM_001310535 RefSeq (protein) NP_001012632 NP_001319 NP_001364115 NP_001364116 NP_001364117 NP_001364118 NP_001364119 NP_001364120 NP_001364121 NP_001364122 NP_001185788 NP_001185789 NP_001185790 NP_001297464 NP_038530 Location (UCSC) Chr 4: 1.21 – 1.25 Mb Chr 5: 33.41 – 33.43 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Function

The CtBP1 protein was originally identified as a human protein that bound a PLDLS motif in the C-terminus of adenovirus E1A proteins. It and the related protein CTBP2 were later shown to function as transcriptional corepressors.^[7] That is, regulatory proteins that bind to sequence-specific DNA-binding proteins and help turn genes off. CtBPs do this by recruiting histone modifying enzymes that add repressive histone marks and remove activating marks. CtBP proteins can also self-associate and presumably bring together gene regulatory complexes.^[8]

CtBP1 is broadly expressed from embryo to adult, while CtBP2 has a somewhat more restricted pattern of expression. CtBPs have multiple biological roles and appear to be most important in regulating the epithelial to mesenchymal transition, as well as influencing metabolism. They do the latter by binding NADH in preference to NAD+, thereby sensing the NADH/NAD+ ratio. When bound, it undergoes a conformational change that allows it to dimerize and associate with its partner proteins and silence specific genes.

During skeletal and T cell development, CtBP1 and CtBP2 associate with the PLDLSL domain of δEF1, a cellular zinc finger-homeodomain protein, and thereby enhances δEF1-induced transcriptional silencing. CtBP also binds the Kruppel-like factors family of zinc finger proteins KLF3, KLF8 and KLF12. In addition, CtBP complexes with CtIP, a 125 kDa protein that recognizes distinctly different protein motifs from CtBP. CtIP binds to the BRCT repeats within the breast cancer gene BRCA1 and enables CtBP to influence BRCA1 activity. Both proteins can also interact with a polycomb group protein complex which participates in regulation of gene expression during development. Alternative splicing of transcripts from this gene results in multiple transcript variants.^[9]

C-terminal-binding protein interacting protein (CtIP) is a binding partner with CtBP, which contribute to transcription repression and cell cycle regulation, and which have a role in the cellular response to DNA damage.^[10]

Interactions

CTBP1 has been shown to interact with:

• ACTL6B,^[11]
• ARF,^[12]
• EVI1^[13][14]
• FOXP2,^[15]
• HDAC1,^[16][17][18]
• IKZF1,^[19]
• IKZF4,^[20]
• KLF3,^[7]
• KLF8,^[21]
• Mdm2,^[22]
• MLL,^[23]
• NRIP1,^[24][25]
• Pinin,^[26]
• RBBP8,^[5][27] and
• TGIF1.^[17]
• GATA1.^[28][29]

References

1. GRCh38: Ensembl release 89: ENSG00000159692 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000037373 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Schaeper U, Subramanian T, Lim L, Boyd JM, Chinnadurai G (April 1998). "Interaction between a cellular protein that binds to the C-terminal region of adenovirus E1A (CtBP) and a novel cellular protein is disrupted by E1A through a conserved PLDLS motif". J. Biol. Chem. 273 (15): 8549–52. doi:10.1074/jbc.273.15.8549. PMID 9535825.
6. Ding B, Yuan F, Damle PK, Grossman SR (2020). "CtBP determines ovarian cancer cell fate through repression of death receptors". Cell Death & Disease. 11 (4): 286. doi:10.1038/s41419-020-2455-7. PMC 7181866. PMID 32332713.
7. Turner J, Crossley M (September 1998). "Cloning and characterization of mCtBP2, a co-repressor that associates with basic Krüppel-like factor and other mammalian transcriptional regulators". EMBO J. 17 (17): 5129–40. doi:10.1093/emboj/17.17.5129. PMC 1170841. PMID 9724649.
8. Chinnadurai G (2002). "CtBP, an unconventional transcriptional corepressor in development and oncogenesis". Mol. Cell. 9 (2): 213–24. doi:10.1016/S1097-2765(02)00443-4. PMID 11864595.
9. "Entrez Gene: CTBP1 C-terminal binding protein 1".
10. Bruton RK, Rasti M, Mapp KL, Grand R (2007). "C-terminal-binding protein interacting protein binds directly to adenovirus early region 1A through its N-terminal region and conserved region 3". Oncogene. 26 (53): 7467–7479. doi:10.1038/sj.onc.1210551. PMID 17546052.
11. Oma Y, Nishimori K, Harata M (February 2003). "The brain-specific actin-related protein ArpN alpha interacts with the transcriptional co-repressor CtBP". Biochem. Biophys. Res. Commun. 301 (2): 521–8. doi:10.1016/S0006-291X(02)03073-5. PMID 12565893.
12. Paliwal S, Pande S, Kovi RC, Sharpless NE, Bardeesy N, Grossman SR (March 2006). "Targeting of C-Terminal Binding Protein (CtBP) by ARF Results in p53-Independent Apoptosis". Mol. Cell. Biol. 26 (6): 2360–72. doi:10.1128/MCB.26.6.2360-2372.2006. PMC 1430274. PMID 16508011.
13. Chakraborty S, Senyuk V, Sitailo S, Chi Y, Nucifora G (November 2001). "Interaction of EVI1 with cAMP-responsive element-binding protein-binding protein (CBP) and p300/CBP-associated factor (P/CAF) results in reversible acetylation of EVI1 and in co-localization in nuclear speckles". J. Biol. Chem. 276 (48): 44936–43. doi:10.1074/jbc.M106733200. PMID 11568182.
14. Izutsu K, Kurokawa M, Imai Y, Maki K, Mitani K, Hirai H (May 2001). "The corepressor CtBP interacts with Evi-1 to repress transforming growth factor beta signaling". Blood. 97 (9): 2815–22. doi:10.1182/blood.V97.9.2815. PMID 11313276.
15. Li S, Weidenfeld J, Morrisey EE (January 2004). "Transcriptional and DNA Binding Activity of the Foxp1/2/4 Family Is Modulated by Heterotypic and Homotypic Protein Interactions". Mol. Cell. Biol. 24 (2): 809–22. doi:10.1128/MCB.24.2.809-822.2004. PMC 343786. PMID 14701752.
16. Zhang CL, McKinsey TA, Lu JR, Olson EN (January 2001). "Association of COOH-terminal-binding protein (CtBP) and MEF2-interacting transcription repressor (MITR) contributes to transcriptional repression of the MEF2 transcription factor". J. Biol. Chem. 276 (1): 35–9. doi:10.1074/jbc.M007364200. PMID 11022042.
17. Melhuish TA, Wotton D (December 2000). "The interaction of the carboxyl terminus-binding protein with the Smad corepressor TGIF is disrupted by a holoprosencephaly mutation in TGIF". J. Biol. Chem. 275 (50): 39762–6. doi:10.1074/jbc.C000416200. PMID 10995736.
18. Sundqvist A, Sollerbrant K, Svensson C (June 1998). "The carboxy-terminal region of adenovirus E1A activates transcription through targeting of a C-terminal binding protein-histone deacetylase complex". FEBS Lett. 429 (2): 183–8. Bibcode:1998FEBSL.429..183S. doi:10.1016/S0014-5793(98)00588-2. PMID 9650586. S2CID 20660291.
19. Koipally J, Georgopoulos K (June 2000). "Ikaros interactions with CtBP reveal a repression mechanism that is independent of histone deacetylase activity". J. Biol. Chem. 275 (26): 19594–602. doi:10.1074/jbc.M000254200. PMID 10766745.
20. Perdomo J, Crossley M (December 2002). "The Ikaros family protein Eos associates with C-terminal-binding protein corepressors". Eur. J. Biochem. 269 (23): 5885–92. doi:10.1046/j.1432-1033.2002.03313.x. PMID 12444977.
21. van Vliet J, Turner J, Crossley M (May 2000). "Human Krüppel-like factor 8: a CACCC-box binding protein that associates with CtBP and represses transcription". Nucleic Acids Res. 28 (9): 1955–62. doi:10.1093/nar/28.9.1955. PMC 103308. PMID 10756197.
22. Mirnezami AH, Campbell SJ, Darley M, Primrose JN, Johnson PW, Blaydes JP (July 2003). "Hdm2 recruits a hypoxia-sensitive corepressor to negatively regulate p53-dependent transcription" (PDF). Curr. Biol. 13 (14): 1234–9. Bibcode:2003CBio...13.1234M. doi:10.1016/S0960-9822(03)00454-8. PMID 12867035. S2CID 2451241.
23. Xia ZB, Anderson M, Diaz MO, Zeleznik-Le NJ (July 2003). "MLL repression domain interacts with histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor C-terminal-binding protein". Proc. Natl. Acad. Sci. U.S.A. 100 (14): 8342–7. Bibcode:2003PNAS..100.8342X. doi:10.1073/pnas.1436338100. PMC 166231. PMID 12829790.
24. Castet A, Boulahtouf A, Versini G, Bonnet S, Augereau P, Vignon F, Khochbin S, Jalaguier S, Cavaillès V (2004). "Multiple domains of the Receptor-Interacting Protein 140 contribute to transcription inhibition". Nucleic Acids Res. 32 (6): 1957–66. doi:10.1093/nar/gkh524. PMC 390375. PMID 15060175.
25. Perissi V, Scafoglio C, Zhang J, Ohgi KA, Rose DW, Glass CK, Rosenfeld MG (March 2008). "TBL1 and TBLR1 Phosphorylation on Regulated Gene Promoters Overcomes Dual CtBP and NCoR/SMRT Transcriptional Repression Checkpoints". Mol. Cell. 29 (6): 755–66. doi:10.1016/j.molcel.2008.01.020. PMC 2364611. PMID 18374649.
26. Alpatov R, Munguba GC, Caton P, Joo JH, Shi Y, Shi Y, Hunt ME, Sugrue SP (December 2004). "Nuclear Speckle-Associated Protein Pnn/DRS Binds to the Transcriptional Corepressor CtBP and Relieves CtBP- Mediated Repression of the E-Cadherin Gene". Mol. Cell. Biol. 24 (23): 10223–35. doi:10.1128/MCB.24.23.10223-10235.2004. PMC 529029. PMID 15542832.
27. Li S, Chen PL, Subramanian T, Chinnadurai G, Tomlinson G, Osborne CK, Sharp ZD, Lee WH (April 1999). "Binding of CtIP to the BRCT repeats of BRCA1 involved in the transcription regulation of p21 is disrupted upon DNA damage". J. Biol. Chem. 274 (16): 11334–8. doi:10.1074/jbc.274.16.11334. PMID 10196224.
28. Snow JW, Kim J, Currie CR, Xu J, Orkin SH (September 2010). "Sumoylation regulates interaction of FOG1 with C-terminal-binding protein (CTBP)". The Journal of Biological Chemistry. 285 (36): 28064–75. doi:10.1074/jbc.M109.096909. PMC 2934671. PMID 20587419.
29. Katsumura KR, Bresnick EH (April 2017). "The GATA factor revolution in hematology". Blood. 129 (15): 2092–2102. doi:10.1182/blood-2016-09-687871. PMC 5391619. PMID 28179282.

Further reading

• Chinnadurai G (2002). "CtBP, an unconventional transcriptional corepressor in development and oncogenesis". Mol. Cell. 9 (2): 213–24. doi:10.1016/S1097-2765(02)00443-4. PMID 11864595.
• Schaeper U, Boyd JM, Verma S, Uhlmann E, Subramanian T, Chinnadurai G (1995). "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. Natl. Acad. Sci. U.S.A. 92 (23): 10467–71. Bibcode:1995PNAS...9210467S. doi:10.1073/pnas.92.23.10467. PMC 40632. PMID 7479821.
• Boyd JM, Subramanian T, Schaeper U, La Regina M, Bayley S, Chinnadurai G (1993). "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 (2): 469–78. doi:10.1002/j.1460-2075.1993.tb05679.x. PMC 413230. PMID 8440238.
• Schaeper U, Subramanian T, Lim L, Boyd JM, Chinnadurai G (1998). "Interaction between a cellular protein that binds to the C-terminal region of adenovirus E1A (CtBP) and a novel cellular protein is disrupted by E1A through a conserved PLDLS motif". J. Biol. Chem. 273 (15): 8549–52. doi:10.1074/jbc.273.15.8549. PMID 9535825.
• Sundqvist A, Sollerbrant K, Svensson C (1998). "The carboxy-terminal region of adenovirus E1A activates transcription through targeting of a C-terminal binding protein-histone deacetylase complex". FEBS Lett. 429 (2): 183–8. Bibcode:1998FEBSL.429..183S. doi:10.1016/S0014-5793(98)00588-2. PMID 9650586. S2CID 20660291.
• Fuks F, Milner J, Kouzarides T (1998). "BRCA2 associates with acetyltransferase activity when bound to P/CAF". Oncogene. 17 (19): 2531–4. doi:10.1038/sj.onc.1202475. PMID 9824164. S2CID 9999991.
• Sewalt RG, Gunster MJ, van der Vlag J, Satijn DP, Otte AP (1999). "C-Terminal Binding Protein Is a Transcriptional Repressor That Interacts with a Specific Class of Vertebrate Polycomb Proteins". Mol. Cell. Biol. 19 (1): 777–87. doi:10.1128/MCB.19.1.777. PMC 83934. PMID 9858600.
• Li S, Chen PL, Subramanian T, Chinnadurai G, Tomlinson G, Osborne CK, Sharp ZD, Lee WH (1999). "Binding of CtIP to the BRCT repeats of BRCA1 involved in the transcription regulation of p21 is disrupted upon DNA damage". J. Biol. Chem. 274 (16): 11334–8. doi:10.1074/jbc.274.16.11334. PMID 10196224.
• Postigo AA, Dean DC (1999). "ZEB represses transcription through interaction with the corepressor CtBP". Proc. Natl. Acad. Sci. U.S.A. 96 (12): 6683–8. Bibcode:1999PNAS...96.6683P. doi:10.1073/pnas.96.12.6683. PMC 21975. PMID 10359772.
• Criqui-Filipe P, Ducret C, Maira SM, Wasylyk B (1999). "Net, a negative Ras-switchable TCF, contains a second inhibition domain, the CID, that mediates repression through interactions with CtBP and de-acetylation". EMBO J. 18 (12): 3392–403. doi:10.1093/emboj/18.12.3392. PMC 1171419. PMID 10369679.
• Holmes M, Turner J, Fox A, Chisholm O, Crossley M, Chong B (1999). "hFOG-2, a novel zinc finger protein, binds the co-repressor mCtBP2 and modulates GATA-mediated activation". J. Biol. Chem. 274 (33): 23491–8. doi:10.1074/jbc.274.33.23491. PMID 10438528.
• Furusawa T, Moribe H, Kondoh H, Higashi Y (2000). "Identification of CtBP1 and CtBP2 as Corepressors of Zinc Finger-Homeodomain Factor δEF1". Mol. Cell. Biol. 19 (12): 8581–90. doi:10.1128/mcb.19.12.8581. PMC 84984. PMID 10567582.
• Yu X, Baer R (2000). "Nuclear localization and cell cycle-specific expression of CtIP, a protein that associates with the BRCA1 tumor suppressor". J. Biol. Chem. 275 (24): 18541–9. doi:10.1074/jbc.M909494199. PMID 10764811.
• Koipally J, Georgopoulos K (2000). "Ikaros interactions with CtBP reveal a repression mechanism that is independent of histone deacetylase activity". J. Biol. Chem. 275 (26): 19594–602. doi:10.1074/jbc.M000254200. PMID 10766745.
• Melhuish TA, Wotton D (2001). "The interaction of the carboxyl terminus-binding protein with the Smad corepressor TGIF is disrupted by a holoprosencephaly mutation in TGIF". J. Biol. Chem. 275 (50): 39762–6. doi:10.1074/jbc.C000416200. PMID 10995736.
• Zhang CL, McKinsey TA, Lu JR, Olson EN (2001). "Association of COOH-terminal-binding protein (CtBP) and MEF2-interacting transcription repressor (MITR) contributes to transcriptional repression of the MEF2 transcription factor". J. Biol. Chem. 276 (1): 35–9. doi:10.1074/jbc.M007364200. PMID 11022042.
• Izutsu K, Kurokawa M, Imai Y, Maki K, Mitani K, Hirai H (2001). "The corepressor CtBP interacts with Evi-1 to repress transforming growth factor beta signaling". Blood. 97 (9): 2815–22. doi:10.1182/blood.V97.9.2815. PMID 11313276.
• Palmer S, Brouillet JP, Kilbey A, Fulton R, Walker M, Crossley M, Bartholomew C (2001). "Evi-1 transforming and repressor activities are mediated by CtBP co-repressor proteins". J. Biol. Chem. 276 (28): 25834–40. doi:10.1074/jbc.M102343200. PMID 11328817.
• Schuierer M, Hilger-Eversheim K, Dobner T, Bosserhoff AK, Moser M, Turner J, Crossley M, Buettner R (2001). "Induction of AP-2alpha expression by adenoviral infection involves inactivation of the AP-2rep transcriptional corepressor CtBP1". J. Biol. Chem. 276 (30): 27944–9. doi:10.1074/jbc.M100070200. PMID 11373277.

External links

• Human CTBP1 genome location and CTBP1 gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: Q13363 (C-terminal-binding protein 1) at the PDBe-KB.