C-terminal binding proteins: central players in development and disease

Stankiewicz, Trisha R.; Gray, Josie J.; Winter, Aimee N.; Linseman, Daniel A.

doi:10.1515/bmc-2014-0027

Cited by 77 publications

(94 citation statements)

References 131 publications

(222 reference statements)

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“…The CTBP binding site in FOXP2 was previously suggested to be a PLNLV motif at residues 422–426, due to the similarity of this motif to the consensus CTBP-binding motif PXDLS (Fig. 4a) [24, 36]. The PLNLV motif is conserved in FOXP1 but not FOXP4, consistent with the lack of interaction between CTBP1 and FOXP4 [24] (Fig.…”

Section: Resultssupporting

confidence: 65%

“…Relatively, little is known about the interaction partners of FOXP2; however, proteins of the CTBP family have been identified as candidate FOXP2 interactors in multiple independent yeast two-hybrid screens [24, 32–34]. The CTBP family consists of two proteins, CTBP1 and CTBP2, which function as co-repressors for multiple transcription factors [35, 36]. The interaction between FOXP2 and CTBP1 has previously been validated by us using the BRET assay, and by others via co-immunoprecipitation, but the interaction with CTBP2 has not yet been confirmed [19, 24].…”

Section: Resultsmentioning

confidence: 99%

“…The CTBPs are conserved vertebrate proteins that interact with several different transcription factors and mediate transcriptional repression primarily through recruitment of the histone deacetylases HDAC1/2 [36]. The CTBPs are widely expressed during embryonic development and have essential and partially overlapping roles in the development of multiple organs [35, 36].…”

Section: Discussionmentioning

confidence: 99%

“…The CTBPs are widely expressed during embryonic development and have essential and partially overlapping roles in the development of multiple organs [35, 36]. They are expressed in the brain from a very early stage, although their specific roles in neurodevelopment have not been extensively investigated [35, 36]. CTBPs may therefore be key players in FOXP2- and FOXP1-mediated transcriptional repression across multiple organs and developmental stages, including in neurodevelopment.…”

Section: Discussionmentioning

confidence: 99%

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Functional characterization of rare FOXP2 variants in neurodevelopmental disorder

Estruch

Graham

Chinnappa

et al. 2016

J Neurodevelop Disord

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BackgroundHeterozygous disruption of FOXP2 causes a rare form of speech and language impairment. Screens of the FOXP2 sequence in individuals with speech/language-related disorders have identified several rare protein-altering variants, but their phenotypic relevance is often unclear. FOXP2 encodes a transcription factor with a forkhead box DNA-binding domain, but little is known about the functions of protein regions outside this domain.MethodsWe performed detailed functional analyses of seven rare FOXP2 variants found in affected cases, including three which have not been previously characterized, testing intracellular localization, transcriptional regulation, dimerization, and interaction with other proteins. To shed further light on molecular functions of FOXP2, we characterized the interaction between this transcription factor and co-repressor proteins of the C-terminal binding protein (CTBP) family. Finally, we analysed the functional significance of the polyglutamine tracts in FOXP2, since tract length variations have been reported in cases of neurodevelopmental disorder.ResultsWe confirmed etiological roles of multiple FOXP2 variants. Of three variants that have been suggested to cause speech/language disorder, but never before been characterized, only one showed functional effects. For the other two, we found no effects on protein function in any assays, suggesting that they are incidental to the phenotype. We identified a CTBP-binding region within the N-terminal portion of FOXP2. This region includes two amino acid substitutions that occurred on the human lineage following the split from chimpanzees. However, we did not observe any effects of these amino acid changes on CTBP binding or other core aspects of FOXP2 function. Finally, we found that FOXP2 variants with reduced polyglutamine tracts did not exhibit altered behaviour in cellular assays, indicating that such tracts are non-essential for core aspects of FOXP2 function, and that tract variation is unlikely to be a highly penetrant cause of speech/language disorder.ConclusionsOur findings highlight the importance of functional characterization of novel rare variants in FOXP2 in assessing the contribution of such variants to speech/language disorder and provide further insights into the molecular function of the FOXP2 protein.Electronic supplementary materialThe online version of this article (doi:10.1186/s11689-016-9177-2) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Functional characterization of rare FOXP2 variants in neurodevelopmental disorder

Estruch

Graham

Chinnappa

et al. 2016

J Neurodevelop Disord

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“…The most common scaffolding protein in the interaction network is TRIM28 (Fig. 5A), followed by TRIM27 (8 interactions), CTBP1 (four interactions), and CTBP2 (three interactions), all of which have been implicated in recruitment of histone modification complexes (Bloor et al 2005;Stankiewicz et al 2014). These findings support a widespread role of C2H2-ZF proteins in chromatin structure and organization.…”

Section: Many C2h2-zf Proteins Interact With Both Transcriptional Actmentioning

confidence: 52%

Multiparameter functional diversity of human C2H2 zinc finger proteins

et al. 2016

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C2H2 zinc finger proteins represent the largest and most enigmatic class of human transcription factors. Their C2H2-ZF arrays are highly variable, indicating that most will have unique DNA binding motifs. However, most of the binding motifs have not been directly determined. In addition, little is known about whether or how these proteins regulate transcription. Most of the ∼700 human C2H2-ZF proteins also contain at least one KRAB, SCAN, BTB, or SET domain, suggesting that they may have common interacting partners and/or effector functions. Here, we report a multifaceted functional analysis of 131 human C2H2-ZF proteins, encompassing DNA binding sites, interacting proteins, and transcriptional response to genetic perturbation. We confirm the expected diversity in DNA binding motifs and genomic binding sites, and provide motif models for 78 previously uncharacterized C2H2-ZF proteins, most of which are unique. Surprisingly, the diversity in protein–protein interactions is nearly as high as diversity in DNA binding motifs: Most C2H2-ZF proteins interact with a unique spectrum of co-activators and co-repressors. Thus, multiparameter diversification likely underlies the evolutionary success of this large class of human proteins.

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CircIMMP2L promotes esophageal squamous cell carcinoma malignant progression via CtBP1 nuclear retention dependent epigenetic modification

Liang

Mao

Wang

et al. 2021

Clinical & Translational Med

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Background Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers. The two major lethal causes of ESCC are diagnosis at an advanced stage and lymph node metastasis (LNM). Circular RNAs (circRNAs) play critical regulatory roles in cancer progression, though, largely through unclear mechanisms. However, the character of circRNAs in the malignant progression of ESCC remains unclear. Methods The circRNA microarray was used to explore the circRNAs that were differentially expressed between ESCC and paired adjacent normal tissues. The function of circIMMP2L was validated by gain or loss of function assays. Pull‐down, RNA immunoprecipitation assays were used to demonstrate the biological mechanism of circIMMP2L. Tissue microarray (TMA), specimen, and paired plasma were investigated to evaluate the clinical significance of circIMMP2L. Results CircIMMP2L, commonly upregulated in tumor and plasma from advanced‐stage ESCC patients and LNM patients, predicts poorer patient survival. CircIMMP2L was also found to be a significant indicator for LNM, even in the T1 stage of ESCC. CircIMMP2L depletion suppressed the malignant progression of ESCC both in vitro and in vivo. Mechanistically, cytoplasmic circIMMP2L interacted with CtBP1 and facilitated the nuclear retention of CtBP1 in a CtBP2‐independent manner. Moreover, circIMMP2L promoted the interaction of CtBP1 with HDAC1 in the nucleus, which is essential for epigenetic remodeling and transcriptional suppression of E‐cadherin and p21. Conclusions These findings demonstrated that circIMMP2L promotes the malignant progression of ESCC mediated by CtBP1 nuclear retention and is a robust biomarker for the diagnosis, prognosis, and LNM in ESCC. Further, the findings extend our knowledge about the mechanism of circRNA regulation of gene transcription through epigenetics.

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C-terminal binding proteins: central players in development and disease

Cited by 77 publications

References 131 publications

Functional characterization of rare FOXP2 variants in neurodevelopmental disorder

Functional characterization of rare FOXP2 variants in neurodevelopmental disorder

Multiparameter functional diversity of human C2H2 zinc finger proteins

CircIMMP2L promotes esophageal squamous cell carcinoma malignant progression via CtBP1 nuclear retention dependent epigenetic modification

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