A Mechanism of COOH–Terminal Binding Protein–Mediated Repression

Meloni, Alison R.; Lai, Chun-Hsiang; Yao, Tso‐Pang; Nevins, Joseph R.

doi:10.1158/1541-7786.mcr-05-0088

Cited by 15 publications

(13 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is possible that CtBP1, unlike CtBP2, uses additional HDAC-independent mechanisms (see below). Previous reports have suggested that CtBP1 antagonizes the activities of global trans activators such as p300/CBP and P/CAF (26,34,48).…”

Section: Discussionmentioning

confidence: 98%

“…The potential role of CtBP1 in targeting the sumoylation machinery to the chromatin is an attractive possibility and remains to be explored. CtBP1 has been reported to antagonize the activity of positive transcription factors such as p300/CBP (26,34,48). Since sumoylation of p300 has been reported to reverse its transcriptional function (14), the possibility that CtBP1 inhibits the activity of p300/CBP through sumoylation also remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Role of the PLDLS-Binding Cleft Region of CtBP1 in Recruitment of Core and Auxiliary Components of the Corepressor Complex

Kuppuswamy

Vijayalingam

Zhao

et al. 2008

Molecular and Cellular Biology

108

141

View full text Add to dashboard Cite

C-terminal binding protein (CtBP) family proteins CtBP1 and CtBP2 are highly homologous transcriptional corepressors and are recruited by a large number of transcription factors to mediate sequence-specific transcriptional repression. In addition to DNA-binding repressors, the nuclear protein complex of CtBP1 consists of enzymatic constituents such as histone deacetylases (HDAC1/2), histone methyl transferases (HMTases; G9a and GLP), and the lysine-specific demethylase (LSD1). Additionally, CtBPs also recruit the components of the sumoylation machinery. The CtBPs contain two different unique structural elements, a hydrophobic cleft, with which factors that contain motifs related to the E1A PLDLS motif bind, and a surface groove that binds with factors containing motifs related to the sequence RRTGXPPXL (RRT motif). By structure-based functional dissection of CtBP1, we show that the PLDLS-binding cleft region functions as the primary recruitment center for DNA-binding factors and for the core and auxiliary enzymatic constituents of the CtBP1 corepressor complex. We identify HDAC1/2, CoREST/LSD1, and Ubc9 (E2) as the core constituents of the CtBP1 complex, and these components interact with the PLDLS cleft region through non-PLDLS interactions. Among the CtBP core constituents, HDACs contribute predominantly to the repression activity of CtBP1. The auxiliary components include an HMTase complex (G9a/Wiz/CDYL) and two SUMO E3 ligases, HPC2 and PIAS1. The interaction of auxiliary components with CtBP1 is excluded by PLDLS (E1A)-mediated interactions. Although monomeric CtBP1 is proficient in the recruiting of both core and auxiliary components, NAD(H)-dependent dimerization is required for transcriptional repression. We also provide evidence that CtBP1 functions as a platform for sumoylation of cofactors.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Role of the PLDLS-Binding Cleft Region of CtBP1 in Recruitment of Core and Auxiliary Components of the Corepressor Complex

Kuppuswamy

Vijayalingam

Zhao

et al. 2008

Molecular and Cellular Biology

108

141

View full text Add to dashboard Cite

show abstract

“…This model is suggested by the finding that K10R and 3KR mutants of CtBP2 were more active in repression of the E-cadherin promoter. There is a precedent for such a model, as CtBP has been reported to sequester and inhibit the transcriptional activities of positive transcriptional regulators such as p300/CBP (25,48,49) and nuclear ␤-catenin (50). Alternatively, cytoplasmically localized non-acetylated CtBP2 may help regulate cytoplasmic functions, which may have an indirect effect on E-cadherin promoter.…”

Section: Discussionmentioning

confidence: 99%

“…In CtBP1, the existence of a protein interaction surface other than the PXDLSbinding pocket has been inferred (51). Similarly, regions of p300, in addition to the bromodomain have been implicated in interaction with CtBP1 (48,49).…”

Section: Discussionmentioning

confidence: 99%

Acetylation by p300 Regulates Nuclear Localization and Function of the Transcriptional Corepressor CtBP2

Zhao

Subramanian

Zhou

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

CtBP family members, CtBP1 and CtBP2, are unique transcriptional regulators that adapt a metabolic enzyme fold, and their activities are regulated by NAD(H)-binding. CtBP1 is both cytoplasmic and nuclear, and its subcellular localization is regulated by sumoylation, phosphorylation, and binding to a PDZ protein. In contrast, we showed that CtBP2 is exclusively nuclear. CtBP1 and CtBP2 are highly similar, but differ at the N-terminal 20 amino acid region. Substitution of the N-terminal domain of CtBP1 with the corresponding CtBP2 domain confers a dominant nuclear localization pattern to CtBP1. The N-terminal domain of CtBP2 contains three Lys residues. Our results show that these Lys residues are acetylated by the nuclear acetylase p300. Although all three Lys residues of CtBP2 (Lys-6, Lys-8, and Lys-10) appear to be acetylated, acetylation of Lys-10 is critical for nuclear localization. CtBP2 with a single amino acid substitution at Lys-10 (K10R) is predominantly localized in the cytoplasm. The cytoplasmic localization of the K10R mutant is correlated with enhanced nuclear export that is inhibited by leptomycin B. Furthermore, lack of acetylation at Lys-10 renders CtBP2 to be more efficient in repression of the E-cadherin promoter. Our studies have revealed the important roles of acetylation in regulating subcellular localization and transcriptional activity of CtBP2.

show abstract

“…This shows a complementary mechanism by which CtBP represses transcription. [14][15][16] CtBP proteins have structural similarities to NAD + -dependent D-hydroxyacid dehydrogenases. They form homo-and heterodimers with each subunit consisting of a nucleotide-binding domain (capable of binding NAD + or NADH) and the substrate-binding domain at the N-terminus including the cleft that interacts with the PXDLS peptide.…”

Section: Introductionmentioning

confidence: 99%

The Transcriptional Co-Repressor C-Terminal Binding Protein (CtBP) Associates with Centrosomes During Mitosis

Spyer¹,

Allday²

2006

Cell Cycle

View full text Add to dashboard Cite

ABBREVIATIONS CtBPC-terminal binding protein BARS Brefeldin A ribosylation substrate BFA Brefeldin A GST Glutathione-S-transferase ACKNOWLEDGEMENTSWe are very grateful to the Wellcome Trust for supporting this research through a programme grant to M.J.A. ReportThe Transcriptional Co-Repressor C-Terminal Binding Protein (CtBP) Associates with Centrosomes During Mitosis ABSTRACTCtBP is a corepressor of transcription that acts by inhibiting coactivators and recruiting to promoter control elements (via interactions with DNA-binding transcription factors) a complex of proteins that modify histones, repress transcription and silence gene expression. There are two highly homologous genes, CtBP1 and CtBP2 that encode CtBP. In addition, a CtBP1-related protein has been described that has 11 fewer amino acids at its N-terminus than CtBP1. This variant of CtBP1-known as CtBP3 or BARS [Brefeldin A (BFA) ribosylated substrate]-plays a critical role in the fragmentation of the Golgi complex at the onset of mitosis. Although there are some reports of CtBP with a cytoplasmic distribution after transfection, it is unclear how in normal cells a nuclear corepressor regulates the behavior of the Golgi complex at the onset of mitosis. Using polyclonal rabbit antibodies that were raised against a human CtBP1-GST fusion-protein, here we show by immunofluorescence laser-scanning confocal microscopy that in mitotic cells a species of CtBP becomes associated with the centrosomes at the onset of prophase and then throughout mitosis. The association can be seen in both cycling mitotic cells and nocodazole-arrested cells. The interaction was confirmed by coimmunoprecipitation and centrosome isolation. Since centrosomes are considered to be the organizing centre for Golgi morphogenesis, the interaction demonstrated here may explain how a nuclear corepressor of transcription can exert a regulatory effect on the Golgi complex at a specific stage of the cell cycle.

show abstract

A Mechanism of COOH–Terminal Binding Protein–Mediated Repression

Cited by 15 publications

References 71 publications

Role of the PLDLS-Binding Cleft Region of CtBP1 in Recruitment of Core and Auxiliary Components of the Corepressor Complex

Role of the PLDLS-Binding Cleft Region of CtBP1 in Recruitment of Core and Auxiliary Components of the Corepressor Complex

Acetylation by p300 Regulates Nuclear Localization and Function of the Transcriptional Corepressor CtBP2

The Transcriptional Co-Repressor C-Terminal Binding Protein (CtBP) Associates with Centrosomes During Mitosis

Contact Info

Product

Resources

About