Interaction of E2F7 Transcription Factor with E2F1 and C-terminal-binding Protein (CtBP) Provides a Mechanism for E2F7-dependent Transcription Repression

Liu, Beiyu; Shats, Igor; Gatza, Michael L.; Nevins, Joseph R.

doi:10.1074/jbc.m113.467506

Cited by 35 publications

(31 citation statements)

References 41 publications

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“…Although we identified E2F7 in the CtBP2-protein complex, we showed that it interacts with CtBP1 as well. During the preparation of this manuscript another report identified CtBP1 and CtBP2 as E2F7-interacting proteins [23]. Our results indicate that E2F7 interacts with the hydrophobic cleft region of CtBP since a mutation of a critical residue A58 of CtBP2 (corresponding to A52 of CtBP1) within the hydrophobic cleft region abolished E2F7 interaction.…”

Section: Discussionmentioning

confidence: 61%

CtBP2 proteome: Role of CtBP in E2F7-mediated repression and cell proliferation

et al. 2014

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C-terminal binding protein (CtBP) family transcriptional corepressors include CtBP1 and CtBP2. While CtBP1 and CtBP2 share significant amino acid sequence homology, CtBP2 possesses a unique N-terminal domain that is modified by acetylation and contributes to exclusive nuclear localization. Although CtBP1 and CtBP2 are functionally redundant for certain activities during vertebrate development, they also perform unique functions. Previous studies have identified several CtBP1-interacting proteins that included other transcriptional corepressors, DNA-binding repressors and histone modifying enzymatic components such as the histone deacetylases and the histone demethylase LSD-1. Here, we carried out an unbiased proteomic analysis of CtBP2-associated proteins and discovered the association of several components of the CtBP1 proteome as well as novel interactions. The CtBP2 proteome contained components of the NuRD complex and the E2F family member E2F7. E2F7 interacted with the hydrophobic cleft region of CtBP1 and CtBP2 through a prototypical CtBP binding motif, PIDLS. E2F7 repressed E2F1 transcription, inhibited cell proliferation in a CtBP-dependent fashion. Our study identified CtBP as a corepressor of E2F7 and as a regulator of DNA damage response.

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Section: Discussionmentioning

confidence: 61%

CtBP2 proteome: Role of CtBP in E2F7-mediated repression and cell proliferation

et al. 2014

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“…Both Foxm1 and E2F1 are transcriptional activators involved in cell proliferation (Stender et al 2007; Real et al 2011). E2F7 represses the activity of E2F1 by binding to E2F1-responsive genes (De Bruin et al 2003; Liu et al 2013). However, at 24 h, E2F7 is only enriched in the set of upregulated genes.…”

Section: Resultsmentioning

confidence: 99%

Information-dependent enrichment analysis reveals time-dependent transcriptional regulation of the estrogen pathway of toxicity

et al. 2016

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The twenty-first century vision for toxicology involves a transition away from high-dose animal studies to in vitro and computational models (NRC in Toxicity testing in the 21st century: a vision and a strategy, The National Academies Press, Washington, DC, 2007). This transition requires mapping pathways of toxicity by understanding how in vitro systems respond to chemical perturbation. Uncovering transcription factors/signaling networks responsible for gene expression patterns is essential for defining pathways of toxicity, and ultimately, for determining the chemical modes of action through which a toxicant acts. Traditionally, transcription factor identification is achieved via chromatin immunoprecipitation studies and summarized by calculating which transcription factors are statistically associated with up- and downregulated genes. These lists are commonly determined via statistical or fold-change cutoffs, a procedure that is sensitive to statistical power and may not be as useful for determining transcription factor associations. To move away from an arbitrary statistical or fold-change-based cutoff, we developed, in the context of the Mapping the Human Toxome project, an enrichment paradigm called information-dependent enrichment analysis (IDEA) to guide identification of the transcription factor network. We used a test case of activation in MCF-7 cells by 17β estradiol (E2). Using this new approach, we established a time course for transcriptional and functional responses to E2. ERα and ERβ were associated with short-term transcriptional changes in response to E2. Sustained exposure led to recruitment of additional transcription factors and alteration of cell cycle machinery. TFAP2C and SOX2 were the transcription factors most highly correlated with dose. E2F7, E2F1, and Foxm1, which are involved in cell proliferation, were enriched only at 24 h. IDEA should be useful for identifying candidate pathways of toxicity. IDEA outperforms gene set enrichment analysis (GSEA) and provides similar results to weighted gene correlation network analysis, a platform that helps to identify genes not annotated to pathways.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-016-1824-6) contains supplementary material, which is available to authorized users.

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“…Both Foxm1 and E2F1 are transcriptional activators involved in cell proliferation (Stender, Frasor et al 2007, Real, Meo-Evoli et al 2011. E2F7 on the other hand represses the activity of E2F1 by binding to E2F1-responsive genes (De Bruin, Maiti et al 2003, Liu, Shats et al 2013). However at 24h, E2F7 is only enriched in the set of up-regulated genes providing further evidence to the generic cell cycle signature at later times.…”

Section: Cell Cycle Alterations At 24hmentioning

confidence: 99%

Information-dependent Enrichment Analysis Reveals Time-dependent Transcriptional Regulation of the Estrogen Pathway of Toxicity

Pendse

Maertens²,

Rosenberg³

et al. 2016

Preprint

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The twenty-first century vision for toxicology involves a transition away from high-dose animal studies and into in vitro and computational models. This movement requires mapping pathways of toxicity through an understanding of how in vitro systems respond to chemical perturbation. Uncovering transcription factors responsible for gene expression patterns is essential for defining pathways of toxicity, and ultimately, for determining chemical mode of action, through which a toxicant acts. Traditionally this is achieved via chromatin immunoprecipitation studies and summarized by calculating, which transcription factors are statistically associated with the upand down-regulated genes. These lists are commonly determined via statistical or fold-change cutoffs, a procedure that is sensitive to statistical power and may not be relevant to determining transcription factor associations. To move away from an arbitrary statistical or fold-change based cutoffs, we have developed in the context of the Mapping the Human Toxome project, a novel enrichment paradigm called Information Dependent Enrichment Analysis (IDEA) to guide identification of the transcription factor network. We used the test case of endocrine disruption of MCF-7 cells activated by 17β estradiol (E2). Using this new approach, we were able to establish a time course for transcriptional and functional responses to E2. ERα and ERβ are associated with short-term transcriptional changes in response to E2. Sustained exposure leads to the recruitment of an additional ensemble of transcription factors and alteration of cell-cycle machinery. TFAP2C and SOX2 were the transcription factors most highly correlated with dose.

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Interaction of E2F7 Transcription Factor with E2F1 and C-terminal-binding Protein (CtBP) Provides a Mechanism for E2F7-dependent Transcription Repression

Cited by 35 publications

References 41 publications

CtBP2 proteome: Role of CtBP in E2F7-mediated repression and cell proliferation

CtBP2 proteome: Role of CtBP in E2F7-mediated repression and cell proliferation

Information-dependent enrichment analysis reveals time-dependent transcriptional regulation of the estrogen pathway of toxicity

Information-dependent Enrichment Analysis Reveals Time-dependent Transcriptional Regulation of the Estrogen Pathway of Toxicity

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