Zinc finger domain of the human DTX protein adopts a unique RING fold

Miyamoto, Kazuhide; Fujiwara, Yuma; Saito, Kazuki

doi:10.1002/pro.3610

Cited by 6 publications

(3 citation statements)

References 44 publications

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“…In the integral steps of Dx regulated signaling pathway, the formation of homo-multimeric Dx is mediated by the RING-H2 domain (Matsuno et al, 2002). The RING-H2 domain of the DTX family adopts a novel circular fold with eight conserved cysteine and histidine residues, which is different from other RINGs (Miyamoto et al, 2019), whereas DTX3 and DTX3L contain a RING-HC structure with a single histidine (Takeyama et al, 2003). The Deltex C-terminal (DTC) domain, a relatively conserved novel fold and a close neighbor to the RING domain, has been reported in DTX family (Obiero et al, 2012).…”

Section: Structural Features Of Dtx Family In Different Speciesmentioning

confidence: 99%

Functions and Molecular Mechanisms of Deltex Family Ubiquitin E3 Ligases in Development and Disease

Wang

Sun

et al. 2021

Front. Cell Dev. Biol.

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Ubiquitination is a posttranslational modification of proteins that significantly affects protein stability and function. The specificity of substrate recognition is determined by ubiquitin E3 ligase during ubiquitination. Human Deltex (DTX) protein family, which functions as ubiquitin E3 ligases, comprises five members, namely, DTX1, DTX2, DTX3, DTX3L, and DTX4. The characteristics and functional diversity of the DTX family proteins have attracted significant attention over the last decade. DTX proteins have several physiological and pathological roles and are closely associated with cell signal transduction, growth, differentiation, and apoptosis, as well as the occurrence and development of various tumors. Although they have been extensively studied in various species, data on structural features, biological functions, and potential mechanisms of action of the DTX family proteins remain limited. In this review, recent research progress on each member of the DTX family is summarized, providing insights into future research directions and potential strategies in disease diagnosis and therapy.

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Section: Structural Features Of Dtx Family In Different Speciesmentioning

confidence: 99%

Functions and Molecular Mechanisms of Deltex Family Ubiquitin E3 Ligases in Development and Disease

Wang

Sun

et al. 2021

Front. Cell Dev. Biol.

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“…They are involved both in the regulation of targeted-proteins’ function as well as in ubiquitin proteasome system (UPS)-mediated degradation (reviewed by [ 1 ]). RING finger domains found in RNF proteins bind two zinc ions in a “cross-brace” fashion involving a distinctive cysteine and histidine residue-containing motif, a feature previously known to be shared only by zinc-finger DNA-binding proteins [ 2 ]. Despite some DTX proteins having been found overexpressed in cancer, their mechanistic involvement in the underlying pathological process is still at an early stage of investigation [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

The DTX Protein Family: An Emerging Set of E3 Ubiquitin Ligases in Cancer

Scalia

Suma

Carnevale

2023

Cells

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Until recently, Deltex (DTX) proteins have been considered putative E3 ligases, based on the presence of an E3 RING domain in their protein coding sequence. The human DTX family includes DTX1, DTX2, DTX3, DTX3L and DTX4. Despite the fact that our knowledge of this class of E3-ubiquitin ligases is still at an early stage, our understanding of their role in oncogenesis is beginning to unfold. In fact, recently published studies allow us to define specific biological scenarios and further consolidate evidence-based working hypotheses. According to the current evidence, all DTX family members are involved in the regulation of Notch signaling, suggesting a phylogenetically conserved role in the regulation of this pathway. Indeed, additional evidence reveals a wider involvement of these proteins in other signaling complexes and cancer-promoting mechanisms beyond NOTCH signaling. DTX3, in particular, had been known to express two isoform variants (DTX3a and DTX3b). The recent identification and cloning of a third isoform variant in cancer (DTX3c), and its specific involvement in EphB4 degradation in cancer cells, sheds further light on this group of proteins and their specific role in cancer. Herein, we review the cumulative knowledge of this family of E3 Ubiquitin ligases with a specific focus on the potential oncogenic role of DTX isoforms in light of the rapidly expanding findings regarding this protein family’s cellular targets and regulated signaling pathways. Furthermore, using a comparative and bioinformatic approach, we here disclose a new putative motif of a member of this family which may help in understanding the biological and contextual differences between the members of these proteins.

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“…The human Deltex protein family, which functions as ubiquitin E3 ligases, comprises 5 members [i.e., Deltex E3 ubiquitin ligase (DTX) 1, DTX2, DTX3, DTX3L, and DTX4] (18). The DTX family members act as Notch signaling modifiers that control cell fate determination (19), and the pathogenesis and progression of various tumors (18,20,21). The effects of DTX2 on cell differentiation were demonstrated, DTX2 changes the methylation status of H3K9 in the distal regulatory region of the MyoD promoter and directly inhibits demethylase activity of Jumonji domain-containing 1C (JMJD1C) by monoubiquitination to reduce MyoD expression (22).…”

Section: Introductionmentioning

confidence: 99%

Bromodomain containing 4 transcriptionally activated Deltex E3 ubiquitin ligase 2 contributes to glioma progression and predicts an unfavorable prognosis

Wu¹,

Shen²,

Lu³

et al. 2022

Ann Transl Med

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Background: Glioblastoma multiforme (GBM) is the most common type of glioma, and the most aggressive brain malignancy in adults. This study sought to identify novel survival-status related markers, and examine their function in glioma. Methods:The gene expression, survival heatmaps, and Kaplan-Meier survival plots of the genes were analyzed by using gene expression profiling interactive analysis (GEPIA) dataset, Linked Omics. The singlecell data analysis and tumor immune infiltration analysis was conducted by Tumor Immune Estimation Resource (TIMER) dataset. DBTRG and U251 cells with silenced Deltex E3 ubiquitin ligase 2 (DTX2) expression were constructed and used for Cell Counting Kit 8 (CCK-8), and wound healing assay in vitro.Chromatin immunoprecipitation sequencing (ChIP-seq) analysis was used to explore the histone activation marks and transcription factors DTX2 promoter. Dual-luciferase assays were carried out to detect the luciferase activities of bromodomain containing 4 (BRD4) binding to DTX2. Results:We first conducted a survival-status analysis to identify survival status-related genes in The Cancer Genome Atlas GBM and low-grade glioma data sets. A subsequent analysis identified 3 novel prognostic biomarkers; that is, DTX2, cytochrome P450 oxidoreductase, and Williams-Beuren syndrome chromosomal region 16 protein. In the validation Chinese Glioma Genome Atlas data sets, DTX2 showed the best performance, and was examined in a further analysis. Next, 3 short-hairpin ribonucleic acids were designed to silence DTX2 expression, and CCK-8 and wound-healing assays were applied to study the function of DTX2. We found that DTX2-silenced glioma cells exhibited a significant decrease in their growth and migration capabilities. Finally, the molecular basis for increased DTX2 in glioma was investigated via ChIP-Seq analysis and luciferase assays. The analysis revealed that DTX2 was transcriptionally activated by BRD4. Conclusions:In conclusion, BRD4 transcriptionally activates DTX2, contributes to glioma progression, predicts an unfavorable prognosis, and could provide new options for glioma prognosis prediction and treatment.

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Zinc finger domain of the human DTX protein adopts a unique RING fold

Cited by 6 publications

References 44 publications

Functions and Molecular Mechanisms of Deltex Family Ubiquitin E3 Ligases in Development and Disease

Functions and Molecular Mechanisms of Deltex Family Ubiquitin E3 Ligases in Development and Disease

The DTX Protein Family: An Emerging Set of E3 Ubiquitin Ligases in Cancer

Bromodomain containing 4 transcriptionally activated Deltex E3 ubiquitin ligase 2 contributes to glioma progression and predicts an unfavorable prognosis

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