Cryo-EM structure of CtBP2 confirms tetrameric architecture

Jecrois, Anne M.; Dcona, M. Michael; Deng, Xiaoyan; Bandyopadhyay, Dipankar; Grossman, Steven R.; Schiffer, Celia A.; Royer, William E.

doi:10.1016/j.str.2020.11.008

Cited by 17 publications

(22 citation statements)

References 53 publications

(38 reference statements)

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“…F H I G significant differences in CT perfusion parameters and MVD measurements of esophageal cancer with different differentiation levels and pathological types, which was consistent with some foreign literature reports. Tumor growth is mainly supported by new blood vessels with nutrients, which is the pathological basis for tumor cell metastasis and invasion, accounting for approximately 1-10% of the tumor volume (16). According to the definition, BF is mainly determined by the characteristics of tumor BF and the density of microvessels inside the tumor, which reflects the BF in the local area.…”

Section: A B C D Ementioning

confidence: 99%

Correlation between microvessel density (MVD) and multi-spiral CT (MSCT) perfusion parameters of esophageal cancer lesions and the diagnostic value of combined CtBP2 and P16INK4A

Dong

Feng

et al. 2021

J Gastrointest Oncol

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Background: This article aims to analyze the correlation between microvessel density (MVD) and multispiral CT(MSCT) perfusion parameters of esophageal cancer lesions, and the diagnostic value of combining C-terminal binding protein 2 (CtBP2) and P16 inhibitor of cyclin-dependent kinase 4a (P16 INK4A ). Methods: A total of 42 cases of normal esophageal mucosa tissues >5 cm from the cancer tissue were selected as the control group. The expression levels of CtBP2 and P16 INK4A and the values of MSCT perfusion parameters and MVD were compared in the control group and esophageal cancer group. SP immunohistochemical staining was used to detect protein expression levels of CtBP2 and P16 INK4A . The Pearson method was used to analyze the differences and pertinence of MSCT perfusion parameters and MVD in the control group and esophageal cancer group. The receiver operating characteristic (ROC) curve was used to calculate the diagnostic value of CtBP2 and P16 INK4A combined with MVD and MSCT perfusion parameters in esophageal cancer.Results: The positive expression rate of P16 INK4A in the esophageal cancer group was significantly lower than that in the control group. The positive expression rates of CtBP2, blood volume (BV), mean transit time (MTT), surface permeability (permeability surface, PS), and MVD values were significantly higher than those of the control group (P<0.05). There was no significant difference in blood flow (BF) value between the 2 groups (P>0.05). The BF value of the tumor invading the fibrous membrane was significantly higher than that of the non-invading fibrous membrane (P<0.05), and the PS and MVD values of the patients with lymph node metastasis were higher than those without lymph node metastasis (P<0.05). The MSCT perfusion parameters BF and BV were significantly positively correlated with MVD (P<0.05), while MTT, PS, and MVD were not significantly correlated (P>0.05). ROC results showed that the areas under curve (AUC) of CtBP2, P16 INK4A , and MSCT were 0.625, 0.747, and 0.812, respectively. However, the area under the combined detection curve was larger, at 0.869. Conclusions: MSCT perfusion imaging of esophageal cancer lesions can indirectly reflect the angiogenesis of esophageal cancer, and the combination of CtBP2 and P16 INK4A can effectively improve the diagnostic efficiency of the disease.

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Section: A B C D Ementioning

confidence: 99%

Correlation between microvessel density (MVD) and multi-spiral CT (MSCT) perfusion parameters of esophageal cancer lesions and the diagnostic value of combined CtBP2 and P16INK4A

Dong

Feng

et al. 2021

J Gastrointest Oncol

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“…Although oligomerization has most often been considered as dimerization, we ( 41 ) and others ( 34 ) have demonstrated that the primary effect of NAD(H) is to promote assembly of CtBP dimers into tetramers. Moreover, we have recently established the transcriptional relevance of the tetrameric forms by showing that tetramer-destabilizing mutants of CtBP2 are defective for oncogenic activity ( 42 ). Our results here have identified the phosphate groups as central for NAD(H)-linked assembly of tetrameric CtBP and also identified an important difference between CtBP1 and CtBP2 that emanates from a short peptide segment that connects the two subdomains.…”

Section: Discussionmentioning

confidence: 99%

“…In the case of CtBP, substantial evidence exists that oligomerization is linked with NAD(H) binding ( 5 , 29 , 33 , 34 , 35 , 36 ), and dimer-destabilizing mutants inhibit transcriptional function ( 37 , 38 , 39 , 40 ). Although assembly of CtBP has primarily been considered in terms of dimers, there is accumulating evidence that NAD(H) binding triggers the assembly of two CtBP dimers to form tetrameric dimers of dimers ( 33 , 34 , 35 , 41 , 42 ). Moreover, we have recently shown that tetramer-destabilizing mutants of CtBP2 are defective for oncogenic activity ( 42 ).…”

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confidence: 99%

“…Although assembly of CtBP has primarily been considered in terms of dimers, there is accumulating evidence that NAD(H) binding triggers the assembly of two CtBP dimers to form tetrameric dimers of dimers ( 33 , 34 , 35 , 41 , 42 ). Moreover, we have recently shown that tetramer-destabilizing mutants of CtBP2 are defective for oncogenic activity ( 42 ). Here we explore the moieties within NAD(H) that are responsible for promoting tetrameric assembly.…”

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NAD(H) phosphates mediate tetramer assembly of human C-terminal binding protein (CtBP)

Nichols

Schiffer

Royer

2021

Journal of Biological Chemistry

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C-terminal binding proteins (CtBPs) are cotranscriptional factors that play key roles in cell fate. We have previously shown that NAD(H) promotes the assembly of similar tetramers from either human CtBP1 and CtBP2 and that CtBP2 tetramer destabilizing mutants are defective for oncogenic activity. To assist structure-based design efforts for compounds that disrupt CtBP tetramerization, it is essential to understand how NAD(H) triggers tetramer assembly. Here, we investigate the moieties within NAD(H) that are responsible for triggering tetramer formation. Using multiangle light scattering (MALS), we show that ADP is able to promote tetramer formation of both CtBP1 and CtBP2, whereas AMP promotes tetramer assembly of CtBP1, but not CtBP2. Other NAD(H) moieties that lack the adenosine phosphate, including adenosine and those incorporating nicotinamide, all fail to promote tetramer assembly. Our crystal structures of CtBP1 with AMP reveal participation of the adenosine phosphate in the tetrameric interface, pinpointing its central role in NAD(H)-linked assembly. CtBP1 and CtBP2 have overlapping but unique roles, suggesting that a detailed understanding of their unique structural properties might have utility in the design of paralog-specific inhibitors. We investigated the different responses to AMP through a series of site-directed mutants at 13 positions. These mutations reveal a central role for a hinge segment, which we term the 120s hinge that connects the substrate with coenzyme-binding domains and influences nucleotide binding and tetramer assembly. Our results provide insight into suitable pockets to explore in structure-based drug design to interfere with cotranscriptional activity of CtBP in cancer.

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“…The transcriptional co-repressor C-terminal binding protein (CtBP) has been originally named thus, since it binds to the five amino acid domains (PLDLS) at the C-terminus of the adenovirus early region 1A (E1A) protein ( 12 – 14 ). The CtBP protein, including the CtBP1 and CtBP2 protein isoforms, is an evolutionarily conserved transcriptional repressor that has been reported to specifically bind to DNA or protein targets and function as a bridge molecule between DNA-binding proteins and transcriptional repressors, thereby inhibiting gene transcription ( 15 ). In addition, CtBP has been revealed to promote epithelial-mesenchymal transition (EMT) by inhibiting E-cadherin expression ( 14 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

CtBP2 interacts with TGIF to promote the progression of esophageal squamous cell cancer through the Wnt/β‑catenin pathway

Jiang

Huang

et al. 2021

Oncol Rep

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C-terminal-binding protein 2 (CtBP2), a transcriptional co-repressor, plays a main role in tumorigenesis and in the development of multiple tumors. Transforming growth interacting factor (TGIF) is involved in a number of cellular signal transduction pathways and is related to tumor occurrence and development. In the present study, the proteins interacting with CtBP2 were identified and the mechanisms underlying the biological activity of CtBP2 in esophageal squamous cell carcinoma (ESCC) were investigated. The Search Tool for the Retrieval of Interacting Genes (STRING) database was used to search for known proteins interacting with CtBP2, and co-immunoprecipitation (Co-IP) assay was performed to validate the interactions. Reverse transcription-quantitative PCR (RT-qPCR), immunohistochemistry (IHC) and western blot analysis were performed to examine the expression levels of CtBP2 and TGIF in ESCC. The correlation between CtBP2 and TGIF was analyzed using Gene Expression Profiling Interactive Analysis (GEPIA) by Pearson's correlation analysis, and the co-localization of CtBP2 with TGIF in the ECA109 cells was identified using immunofluorescence staining. XAV939 treatment, CCK-8, 5-ethynyl-2'-deoxyuridine (EdU) staining, wound healing and Transwell assays were performed to investigate the signaling pathways involved in the biological activity of CtBP2 in ECA109 cells. According to the results obtained from STRING and Co-IP analysis, an interaction between CtBP2 and TGIF was indicated, and these proteins were co-localized in the nucleus. CtBP2 and TGIF mRNA and protein expression levels were robustly and simultaneously increased in both ESCC tissues and cell lines. There was a direct correlation between CtBP2 and TGIF expression levels in ESCC tissues, and both were significantly associated with metastasis and survival. The TGIF and CtBP2 expression levels were significantly increased or decreased simultaneously, in ECA109 cells transfected with LV-CtBP2 or sh-CtBP2, and vice versa. According to the results of CCK-8 assay, EdU staining and Transwell assay, CtBP2 promoted the proliferation, migration and invasion of ECA109 cells through the Wnt/β-catenin pathway. On the whole, the present study demonstrates that CtBP2 interacts with TGIF and promotes the malignant progression of ESCC through the Wnt/β-catenin pathway.

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Cryo-EM structure of CtBP2 confirms tetrameric architecture

Cited by 17 publications

References 53 publications

Correlation between microvessel density (MVD) and multi-spiral CT (MSCT) perfusion parameters of esophageal cancer lesions and the diagnostic value of combined CtBP2 and P16INK4A

Correlation between microvessel density (MVD) and multi-spiral CT (MSCT) perfusion parameters of esophageal cancer lesions and the diagnostic value of combined CtBP2 and P16INK4A

NAD(H) phosphates mediate tetramer assembly of human C-terminal binding protein (CtBP)

CtBP2 interacts with TGIF to promote the progression of esophageal squamous cell cancer through the Wnt/β‑catenin pathway

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