scholarly journals WW Domain-Containing E3 Ubiquitin Protein Ligase 1: A Self-Disciplined Oncoprotein

2021 ◽  
Vol 9 ◽  
Author(s):  
Linghan Kuang ◽  
Yunhui Jiang ◽  
Chenghua Li ◽  
Yongmei Jiang
Keyword(s):  
Mrna Level ◽  
Migration And Invasion ◽  
Published Data ◽  
Moderate Activity ◽  
Ww Domain ◽  
Promote Cell Proliferation ◽  
Ubiquitin Protein Ligase ◽  
State Association ◽  
Review Reports ◽  
Multiple Domains

WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) is a member of C2-WW-HECT E3 ligase family. Although it may execute carcinostatic actions in some scenarios, WWP1 functions as an oncoprotein under most circumstances. Here, we comprehensively review reports on regulation of WWP1 and its roles in tumorigenesis. We summarize the WWP1-mediated ubiquitinations of diverse proteins and the signaling pathways they involved, as well as the mechanisms how they affect cancer formation and progression. According to our analysis of database, in combination with previous reports, we come to a conclusion that WWP1 expression is augmented in various cancers. Gene amplification, as well as expression regulation mediated by molecules such as non-coding RNAs, may account for the increased mRNA level of WWP1. Regulation of enzymatic activity is another important facet to upregulate WWP1-mediated ubiquitinations. Based on the published data, we conclude that WWP1 employs interactions between multiple domains to autoinhibit its polyubiquitination activity in a steady state. Association of some substrates can partially release certain autoinhibition-related domains and make WWP1 have a moderate activity of polyubiquitination. Some cancer-related mutations can fully disrupt the inhibitory interactions and make WWP1 hyperactive. High expression level or hyperactivation of WWP1 may abnormally enhance polyubiquitinations of some oncoproteins or tumor suppressors, such as ΔNp63α, PTEN and p27, and ultimately promote cell proliferation, survival, migration and invasion in tumorigenesis. Given the dysregulation and oncogenic functions of WWP1 in some cancer types, it is promising to explore some therapeutic inhibitors to tune down its activity.

scholarly journals Oncogenic UBE3C promotes breast cancer progression by activating Wnt/β-catenin signaling

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chen Hang ◽  
Shanojie Zhao ◽  
Tiejun Wang ◽  
Yan Zhang
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Nuclear Accumulation ◽  
Migration And Invasion ◽  
Ubiquitin Protein Ligase ◽  
Novel Target ◽  
First Time ◽  
Breast Tissues

Abstract Background Breast cancer (BrCa) is the most common female malignancy worldwide and has the highest morbidity among all cancers in females. Unfortunately, the mechanisms of BrCa growth and metastasis, which lead to a poor prognosis in BrCa patients, have not been well characterized. Methods Immunohistochemistry (IHC) was performed on a BrCa tissue microarray (TMA) containing 80 samples to evaluate ubiquitin protein ligase E3C (UBE3C) expression. In addition, a series of cellular experiments were conducted to reveal the role of UBE3C in BrCa. Results In this research, we identified UBE3C as an oncogenic factor in BrCa growth and metastasis for the first time. UBE3C expression was upregulated in BrCa tissues compared with adjacent breast tissues. BrCa patients with high nuclear UBE3C expression in tumors showed remarkably worse overall survival (OS) than those with low nuclear expression. Knockdown of UBE3C expression in MCF-7 and MDA-MB-453 BrCa cells inhibited cell proliferation, migration and invasion in vitro, while overexpression of UBE3C in these cells exerted the opposite effects. Moreover, UBE3C promoted β-catenin nuclear accumulation, leading to the activation of the Wnt/β-catenin signaling pathway in BrCa cells. Conclusion Collectively, these results imply that UBE3C plays crucial roles in BrCa development and progression and that UBE3C may be a novel target for the prevention and treatment of BrCa.

scholarly journals Src-1 and SP2 promote the proliferation and epithelial–mesenchymal transition of nasopharyngeal carcinoma

Open Medicine ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. 1061-1069
Author(s):  
Jingjing Zhang ◽  
Yuanyuan Yang ◽  
Hongyu Liu ◽  
Hongyi Hu
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Cell Viability ◽  
Colony Formation ◽  
Epithelial Mesenchymal Transition ◽  
Southern China ◽  
Mrna Level ◽  
Migration And Invasion ◽  
High Morbidity ◽  
Mesenchymal Transition ◽  
Steroid Receptor Coactivator

Abstract Nasopharyngeal carcinoma (NPC) is characterized by high morbidity and morality, especially in Southern China. Transcription factors intensively participate in the initiation and development of NPC. This study aimed to investigate the roles of Src-1 in NPC. mRNA level was determined by qRT-PCR. Western blot was carried out for the protein level. CCK-8 assay was performed to determine cell viability, colony formation for NPC cell proliferation, and transwell for cell migration and invasion ability. The results showed Steroid receptor coactivator 1 (Src-1) was overexpressed in SNE-2 and 6-10B. The expression of Src-1 and SP2 was in positive correlation. Overexpression of Src-1 promoted the cell viability, colony formation, and epithelial–mesenchymal transition (EMT), manifested by the increase of migration and invasion ability, while knockdown of Src-1 exerted opposite effects. Additionally, knockdown or overexpression of SP2 reversed the effects of overexpressed or downregulated Src-1, which was reversed by the depletion of SP2. Moreover, Src-1 interacted with SP2 to regulate EMT-related genes such as E-cad, N-cad, Vimentin, and ZEB1, and proliferation- and apoptosis-related genes, such as bax, cytochrome c, and cleaved caspase3 and bcl-2. Thus, blocking the interaction between Src-1 and SP2 may be a therapeutic target for inhibiting the metastasis of NPC.

scholarly journals Expression Characteristics and Significant Prognostic Values of PGK1 in Breast Cancer

2021 ◽  
Vol 8 ◽  
Author(s):  
Yanping Li ◽  
Shanshan Wang ◽  
Xiaoyuan Zhang ◽  
Rui Yang ◽  
Xiaonan Wei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Mrna Level ◽  
Vital Role ◽  
Migration And Invasion ◽  
Breast Cancer Patients ◽  
Clinicopathologic Characteristics ◽  
Independent Prognostic Marker ◽  
Potential Biomarker ◽  
Mrna And Protein Expression

It was proven that PGK1 plays a vital role in the proliferation, migration, and invasion of human breast cancer. However, the correlation of PGK1 mRNA and protein expression with clinicopathologic characteristics and prognostic values according to various kinds of breast cancer patient classifications remains unsufficient. Here, we analyzed data from the Oncomine database, Breast cancer Gene-Expression Miner v4.5, TNMplot, MuTarget, PrognoScan database, and clinical bioinformatics to investigate PGK1 expression distribution and prognostic value in breast cancer patients. Our study revealed that the mRNA and protein expression levels of PGK1 were up-regulated in various clinicopathologic types of breast cancer. Moreover, the expression of PGK1 was correlated with mutations of common tumor suppressor genes TP53 and CDH1. In addition, we found that high mRNA level of PGK1 was significantly associated with poor OS, RFS, and DMFS. Notably, Cox regressionanalysis showed that PGK1 could be used as an independent prognostic marker. In summary, the aforementioned findings suggested that PGK1 might be not only explored as a potential biomarker, but also combined with TP53/CDH1 for chemotherapy in breast cancer.

Abstract 5494: ADAMTS-7 is Critical for Vascular Smooth Muscle Cell Migration and Neointima Formation in Injured Rat Carotid Artery

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Wei Kong ◽  
Li Wang ◽  
Xue Bai ◽  
Bo Liu ◽  
Yi Zhu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Vascular Injury ◽  
Matrix Protein ◽  
Mrna Level ◽  
Balloon Catheter ◽  
Migration And Invasion ◽  
Neointima Formation ◽  
Subsequent Increase ◽  
Neointimal Thickening

Migration of vascular smooth muscle cells (VSMCs) plays an essential role during vascular development, in response to vascular injury and during atherogenesis. Extensive studies have implicated the importance of extracellular matrix (ECM)-degrading proteinases during VSMCs migration. ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs), a recently described family of proteinases, is capable of degrading vascular ECM proteins. However, the relevance of ADAMTS family members in cardiovascular disease is poorly understood. In this study, we sought to determine whether ADAMTS-7 is involved in VSMC migration and neointima formation in response to vascular injury. Denudation of rat carotid arteries with a balloon catheter led to an initial decrease of ADAMTS-7 protein level in injured compared with sham-operated arteries within the first 24 hours, followed by a subsequent increase during the 4 to 14 days after injury. In primary VSMCs, the pro-inflammatory cytokine TNF-α increased ADAMTS-7 mRNA level through transcriptional factors nuclear factor-kappa B and AP-1. VSMCs infected with ADAMTS-7 adenovirus (Ad-ADAMTS-7) greatly accelerated their migration and invasion in vitro . Conversely, suppression of ADAMTS-7 expression by small interfering RNA (siRNA) markedly retarded VSMC movement by 50% than that with scramble siRNA. At 7 days after injury, the neointimal area of the vascular wall was sixfold greater in Ad-ADAMTS-7-infected than that in Ad-GFP-infected vessels (3.10±0.88 vs. 0.52±0.28 ×10 4 μm 2 , n=8 per group, P <0.05). By contrast, perivascular administration of ADAMTS-7 siRNA, but not scramble siRNA to injured arteries resulted in prolonged ADAMTS-7 silencing and diminished neointimal thickening without affecting medial areas. This inhibitory effect was sustained up to 14 days after injury. As well, ADAMTS-7 mediated degradation of the vascular ECM cartilage oligomeric matrix protein (COMP) in injured vessels, which might facilitate VSMC migration and neointimal thickening. ADAMTS-7 directs VSMC migration and neointima formation and therefore may serve as a novel therapeutic target for vascular restenosis and atherogenesis.

scholarly journals The Role of Cavin3 in the Progression of Lung Cancer and Its Mechanism

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Gaozhong Sun ◽  
Kewei Ni
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Tumor Formation ◽  
Migration And Invasion ◽  
Clinical Value ◽  
Promote Cell Proliferation ◽  
Cancer Tissues

Objective. The purpose of this study was to describe the role of Cavin3 in the progression of lung cancer and its underlying mechanism. Methods. Totally, 200 cases of lung cancer tissues and corresponding paracancer tissues were collected. Cavin3 expression in samples was determined by qRT-PCR, and the correlation with lung cancer stages as well as prognosis was statistically analyzed combined with matched clinical information. To investigate the mechanism of Cavin3 in lung cancer progression, firstly, Cavin3 was detected in lung cancer cell lines A549, PC9, and H520. Then, cells with stable Cavin3 overexpression and Cavin3 knockout were established to determine the effect of Cavin3 overexpression on the mammalian target of rapamycin (mTOR) signaling pathway. Subsequently, cells were harvested for cell proliferation, migration, and invasion assays in vitro, as well as nude mouse transplantation tumor experiment in vivo. Results. Cavin3 was seen to be highly expressed in cancer tissues. Statistical analysis with matched clinical data showed that Cavin3 as a prognostic indicator of lung cancer had important clinical value. In addition, it could be found that high expression of Cavin3 was able to promote cell proliferation, migration, and invasion and also potentiate tumor formation in vivo. Conclusion. Cavin3 was highly expressed in lung cancer, and it was capable to promote cell proliferation, invasion, and migration.

scholarly journals WW domain-containing E3 ubiquitin protein ligase 1 depletion evokes antitumor effect in cutaneous squamous cell carcinoma by inhibiting signal transducer and activator of transcription 3 signaling pathway

2018 ◽  
Vol 46 (7) ◽  
pp. 2898-2912 ◽  
Author(s):  
Yonghua Xia ◽  
Xiao Chang ◽  
Shi Lian ◽  
Wei Zhu
Keyword(s):  
Cell Cycle ◽  
Squamous Cell Carcinoma ◽  
Cell Migration ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Cutaneous Squamous Cell Carcinoma ◽  
Migration And Invasion ◽  
Signal Transducer ◽  
Ubiquitin Protein Ligase ◽  
Transcription 3

Objectives WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) has been implicated in tumor progression. We aimed to investigate the role of WWP1 in cutaneous squamous cell carcinoma (CSCC). Methods WWP1 gene and protein levels were detected using semi-quantitative reverse transcription-polymerase chain reaction, immunohistochemistry and western blotting. The effects of WWP1 on cell cycle, apoptosis, cell migration and invasion were examined by flow cytometry, wound healing and Transwell assays, respectively. The antitumor efficacy of WWP1 small interfering RNA was determined in CSCC tumor xenografts in mice. Results WWP1 expression was significantly higher in CSCC tissues and cells than in normal skin and cells, respectively. WWP1 expression was significantly associated with histological grade, invasion depth and lymph node metastasis in patients with CSCC. High expression predicted metastatic potential and an unfavorable prognosis. WWP1 downregulation suppressed tumor growth in vitro and in vivo, reduced cell migration and invasion, arrested the cell cycle in G0/G1 and induced apoptosis in A431 cells. WWP1 depletion also decreased phosphorylated signal transducer and activator of transcription 3 (STAT3), matrix metalloproteinase-2, cyclin D1 and Bcl-2, but did not affect total STAT3. Conclusions WWP1 is a potential target for the diagnosis, prognosis and therapy of patients with CSCC.

scholarly journals Human Uterine Decidual NK Cells in Women with a History of Early Pregnancy Enhance Angiogenesis and Trophoblast Invasion

2020 ◽  
Vol 2020 ◽  
pp. 1-7 ◽  
Author(s):  
Ningyi Jia ◽  
Jian Li
Keyword(s):  
Early Pregnancy ◽  
Mrna Level ◽  
Trophoblast Invasion ◽  
Migration And Invasion ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Mrna Levels ◽  
History Of ◽  
And Migration ◽  
Primiparous Women

Objective. The present study aimed to identify changes in decidual natural killer (dNK) cells and related cytokines in women who have undergone induced abortions (IAs). The effects of dNK cells on subsequent pregnancies remain unknown. Accordingly, we sought to investigate whether a history of early pregnancy can change dNK cells and facilitate their role in the regulation of angiogenesis and trophoblast invasion. Materials and Methods. dNK cells were obtained from primiparous women who had undergone IA(s) prior to this study and primiparous women who had never been pregnant before this IA (control). Real-time polymerase chain reaction (PCR) was used to measure the mRNA levels of IFN-γ, IP-10, VEGF, and PLGF in dNK cells. The levels of these cytokines were quantified using the enzyme-linked immunosorbent assay. HUVEC and HTR-8/SVneo cells were used to evaluate the angiogenesis, migration, and invasion activities influenced by dNK cells. Results. In dNK cells, the mRNA level of IFN-γ was higher in the control group than that in the IA group. The secretion of IP-10 and VEGF was higher in the IA group compared to the control group. After coculturing with the dNK supernatant, the HTR-8/SVneo cells exhibited better invasiveness and migration in the IA group than those in the control group. Angiogenesis assay demonstrated that dNK cells from IA group might help HUVEC attain better tube formation ability. Conclusion. The findings of this study suggest that a history of early pregnancy has an impact on dNK cells. These trained dNK cells can regulate angiogenesis and trophoblast invasion and migration by promoting the production of certain cytokines.

miR-938 Promotes the Proliferation and Invasion of Prostate Cancer Through Targeting Pleckstrin Homology (PH) Domain Leucine-Rich-Repeats Protein Phosphatase 2 and Forkhead Box O3

2019 ◽  
Vol 9 (5) ◽  
pp. 583-591
Author(s):  
Xin Deng ◽  
Fengye Wang ◽  
Qianjin Zhang ◽  
Xuejian Yang ◽  
Hao Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Protein Phosphatase ◽  
Mrna Level ◽  
Signal Pathway ◽  
Migration And Invasion ◽  
Ph Domain ◽  
Pleckstrin Homology ◽  
Forkhead Box ◽  
Protein Phosphatase 2 ◽  
Leucine Rich Repeats

miR-938 is generally reported to be up-regulated in various cancers, which affect the tumor progression. In the present study, we investigated the biological role and underlying mechanisms of miR-938 in prostate cancer (PCa). PCa is the most common malignant tumor in males with markedly increasing incidence in recent years. Up-regulation of miR-938 occurred in PCa tissues and cell lines at mRNA level. Functional assays were established to demonstrate that miR-938 mimics significantly promoted the proliferation, migration and invasion of PCa cells, while knockdown of miR-938 led to the inhibition. Luciferase activity assay suggested miR-938 directly bound to the 3 UTR of PHLPP2 (Pleckstrin Homology (PH) domain Leucine-rich-repeats Protein Phosphatase 2) and FOXO3 (Forkhead box O3). Our results also showed that the regulation activity of miR-938 on progression of PCa was partially through its negative regulation on PHLPP2 and FOXO3. Our results deciphered the mechanism through which miR-938 promoted the progression of PCa by activation of PI3K/AKT signal pathway. Together, inactivation of PI3K/AKT signal pathway through down-regulation of miR-938 could be an important mechanism in inhibiting PCa progression, thus shedding light on the development of novel anti-tumor therapies for treatment of PCa.

A single WW domain is the predominant mediator of the interaction between the human ubiquitin-protein ligase Nedd4 and the human epithelial sodium channel

2002 ◽  
Vol 361 (3) ◽  
pp. 481-488 ◽  
Author(s):  
J. Shaun LOTT ◽  
Sarah J. CODDINGTON-LAWSON ◽  
Paul H. TEESDALE-SPITTLE ◽  
Fiona J. MCDONALD
Keyword(s):  
The Body ◽  
Single Amino Acid ◽  
Na Channel ◽  
Α Subunit ◽  
Ww Domain ◽  
Ww Domains ◽  
Ubiquitin Protein Ligase ◽  
Single Amino Acid Change ◽  
Domain 3 ◽  
Neuronal Precursor Cell

The activity of the epithelial Na+ channel (ENaC) is required for the maintenance of salt and water balance in the body. Channel activity is regulated by the ubiquitin-protein ligase Nedd4 ['neuronal precursor cell-expressed developmentally down-regulated (gene 4)'] that interacts with the channel via its WW domains. Mutations in channel subunits that disrupt this interaction cause Liddle's syndrome, a severe inherited form of hypertension. In previous studies we showed that WW domains 2, 3 and 4 of human Nedd4 bound to the human ENaC (hENaC) subunits, whereas WW domain 1 did not. Here we extend this observation to determine the binding affinities of the human Nedd4 WW domains for hENaC C-terminal peptides. We show that WW domains 2, 3 and 4 bind with differing affinities to Na+ channel subunit peptides. WW domain 3 has the highest affinity and we predict that WW domain 3 contributes most of the binding because a construct containing the three WW domains bound no better than WW domain 3 alone. Further, a single amino acid change (Arg165 → Thr) in WW domain 1 enables binding to the α subunit of the channel to occur, with an affinity comparable with that of WW domain 4. Differential binding propensities between the various WW domains and Na+ channel subunit peptides are explained on the basis of quantitative structural modelling of the complexes and their isolated components.

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