Drosophila C-terminal Binding Protein Functions as a Context-dependent Transcriptional Co-factor and Interferes with Both Mad and Groucho Transcriptional Repression

Phippen, T.; Sweigart, Andrea L.; Moniwa, Mariko; Krumm, Anton; Davie, James R.; Parkhurst, Susan M.

doi:10.1074/jbc.m004234200

Cited by 79 publications

(91 citation statements)

References 58 publications

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“…Reducing the gene dose of groucho enhances a hairy embryonic segmentation phenotype, as would be predicted by its ability to act as a canonical corepressor (7). Conversely, reducing the gene dose of dCtBP suppresses a hairy embryonic segmentation phenotype, indicating that dCtBP acts to negatively regulate Hairy activity (13,(15)(16)(17). Consistent with this observation, overexpression of Hairy lacking its dCtBP-binding site has an enhanced ability to repress transcription in vivo (13).…”

supporting

confidence: 57%

Drosophila Topors Is a RING Finger-containing Protein That Functions as a Ubiquitin-protein Isopeptide Ligase for the Hairy Basic Helix-Loop-Helix Repressor Protein

Secombe

Parkhurst

2004

Journal of Biological Chemistry

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Transcriptional repression plays an essential role in many aspects of metazoan development. Drosophila hairy is a primary pair-rule gene encoding a basic helixloop-helix class transcriptional repressor that is required for proper segmentation. Previous characterization of Hairy-binding proteins has implicated two different classes of histone deacetylase as mediators of Hairy repression. Here, we present the characterization of a novel Hairy-interacting protein (dTopors) that binds specifically to the basic region of Hairy, but does not affect the ability of Hairy to bind DNA. By reducing the gene dose of dtopors, we demonstrate that it acts genetically as an antagonist of Hairy-mediated transcriptional repression. Consistent with this genetic interaction, we show that that recombinant dTopors protein possesses ubiquitin-protein isopeptide ligase activity in vitro and that dTopors mediates Hairy polyubiquitination and can lead to Hairy degradation. This work provides the first evidence that regulated proteolysis of Hairy is required for correct segmentation.Transcriptional repression is a critical regulatory mechanism for a vast number of developmental processes, including establishment of the Drosophila embryonic body plan. Drosophila segmentation occurs via sequential subdivision of the embryo, leading ultimately to the formation and determination of each body segment. This hierarchy of segmentation gene expression begins with the translation of maternally deposited transcripts (maternal genes), followed by the expression of the zygotic gap, pair-rule, and segment polarity genes. hairy is a pair-rule class gene that encodes a basic helix-loop-helix (bHLH) 1 transcriptional repressor that occupies a key position in the segmentation gene hierarchy: it is one of the first genes to show an overt reiterated periodicity that is central to the establishment of proper embryonic body plan throughout Metazoa (1-5). Hairy is one of a family of 13 structurally related bHLH transcriptional repressors that compose the HES family, which includes seven Enhancer of Split proteins E(spl)m3, E(spl)m5, E(spl)m7, E(spl)m8, E(spl)m␤, and E(spl)m␥ and

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supporting

confidence: 57%

Drosophila Topors Is a RING Finger-containing Protein That Functions as a Ubiquitin-protein Isopeptide Ligase for the Hairy Basic Helix-Loop-Helix Repressor Protein

Secombe

Parkhurst

2004

Journal of Biological Chemistry

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“…CtBP1 does not require NAD ϩ binding nor residues homologous to dehydrogenase domains for co-repressor activity in some (26,28,29), but not all experimental models (12,14,27,30,31). Our data demonstrate that two properties of CtBP (target binding and recruitment of a repression complex) can occur without NAD(H) binding or residues thought to be important for dehydrogenase activity (Figs.…”

Section: Discussionmentioning

confidence: 99%

Nicotinamide Adenine Dinucleotide-induced Multimerization of the Co-repressor CtBP1 Relies on a Switching Tryptophan

Madison

Wirz

Siess³

et al. 2013

Journal of Biological Chemistry

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Background: C-terminal binding protein 1 (CtBP1) assembles into a tetrameric transcriptional co-repressor but how it directs gene expression is not clear. Results: CtBP1 requires NAD(H) for transition into multimers. Its biochemical activities are separable from transcriptional repression. Conclusion: Tryptophan 318 permits CtBP1 to first dimerize and then tetramerize after the binding of NAD(H). Significance: Clarification of how CtBP1 tetramerizes will permit development of CtBP inhibitors to target oncogenesis.

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“…In our report, mutation of two residues (D290A and H312T) predicted to be essential for catalytic activity had no effect on the ability of fly CtBP to potentiate Gal4-Arm transcriptional activation ( Figure 6F). Further complicating the issue is data from experiments expressing the fly CtBP fused to Gal4DBD in mammalian cells (Phippen et al, 2000). In some cells, Gal4-CtBP activated a UAS reporter, while the same reporter was repressed in other cell lines.…”

Section: Ctbp Plays a Direct Role In Transcriptional Activation Of Wnmentioning

confidence: 99%

C-terminal-binding protein directly activates and represses Wnt transcriptional targets in Drosophila

Fang¹,

Li²,

Blauwkamp³

et al. 2006

EMBO J

155

238

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Regulation of Wnt transcriptional targets is thought to occur by a transcriptional switch. In the absence of Wnt signaling, sequence‐specific DNA‐binding proteins of the TCF family repress Wnt target genes. Upon Wnt stimulation, stabilized β‐catenin binds to TCFs, converting them into transcriptional activators. C‐terminal‐binding protein (CtBP) is a transcriptional corepressor that has been reported to inhibit Wnt signaling by binding to TCFs or by preventing β‐catenin from binding to TCF. Here, we show that CtBP is also required for the activation of some Wnt targets in Drosophila. CtBP is recruited to Wnt‐regulated enhancers in a Wnt‐dependent manner, where it augments Armadillo (the fly β‐catenin) transcriptional activation. We also found that CtBP is required for repression of a subset of Wnt targets in the absence of Wnt stimulation, but in a manner distinct from previously reported mechanisms. CtBP binds to Wnt‐regulated enhancers in a TCF‐independent manner and represses target genes in parallel with TCF. Our data indicate dual roles for CtBP as a gene‐specific activator and repressor of Wnt target gene transcription.

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Drosophila C-terminal Binding Protein Functions as a Context-dependent Transcriptional Co-factor and Interferes with Both Mad and Groucho Transcriptional Repression

Cited by 79 publications

References 58 publications

Drosophila Topors Is a RING Finger-containing Protein That Functions as a Ubiquitin-protein Isopeptide Ligase for the Hairy Basic Helix-Loop-Helix Repressor Protein

Drosophila Topors Is a RING Finger-containing Protein That Functions as a Ubiquitin-protein Isopeptide Ligase for the Hairy Basic Helix-Loop-Helix Repressor Protein

Nicotinamide Adenine Dinucleotide-induced Multimerization of the Co-repressor CtBP1 Relies on a Switching Tryptophan

C-terminal-binding protein directly activates and represses Wnt transcriptional targets in Drosophila

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