scholarly journals Post-Translational Modifications in NETosis and NETs-Mediated Diseases

Biomolecules ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 369 ◽  
Author(s):  
Hamam ◽  
Palaniyar
Keyword(s):  
Histone Acetylation ◽  
Cancer Progression ◽  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
Calcium Influx ◽  
Critical Role ◽  
Control Cell ◽  
Clear Understanding ◽  
Post Translational Modifications ◽  
Histone Citrullination

: Neutrophils undergo a unique form of cell death that generates neutrophil extracellular traps (NETs) that may help to neutralize invading pathogens and restore homeostasis. However, uncontrolled NET formation (NETosis) can result in numerous diseases that adversely affect health. Recent studies further elucidate the mechanistic details of the different forms of NETosis and their common end structure, as NETs were constantly found to contain DNA, modified histones and cytotoxic enzymes. In fact, emerging evidence reveal that the post translational modifications (PTMs) of histones in neutrophils have a critical role in regulating neutrophil death. Histone citrullination is shown to promote a rapid form of NET formation independent of NADPH oxidase (NOX), which relies on calcium influx. Interestingly, few studies suggest an association between histone citrullination and other types of PTMs to control cell survival and death, such as histone methylation. Even more exciting is the finding that histone acetylation has a biphasic effect upon NETosis, where histone deacetylase (HDAC) inhibitors promote baseline, NOX-dependent and -independent NETosis. However, increasing levels of histone acetylation suppresses NETosis, and to switch neutrophil death to apoptosis. Interestingly, in the presence of NETosis-promoting stimuli, high levels of HDACis limit both NETosis and apoptosis, and promote neutrophil survival. Recent studies also reveal the importance of the PTMs of neutrophils in influencing numerous pathologies. Histone modifications in NETs can act as a double-edged sword, as they are capable of altering multiple types of neutrophil death, and influencing numerous NET-mediated diseases, such as acute lung injury (ALI), thrombosis, sepsis, systemic lupus erythematosus, and cancer progression. A clear understanding of the role of different PTMs in neutrophils would be important for an understanding of the molecular mechanisms of NETosis, and to appropriately treat NETs-mediated diseases.

scholarly journals STAT3 and STAT5 Activation in Solid Cancers

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1428 ◽  
Author(s):  
Sebastian Igelmann ◽  
Heidi Neubauer ◽  
Gerardo Ferbeyre
Keyword(s):  
Tumor Suppressor ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Critical Role ◽  
Control Cell ◽  
Cytokine Signaling ◽  
Specific Gene ◽  
Mitochondrial Functions ◽  
Context Dependent

The Signal Transducer and Activator of Transcription (STAT)3 and 5 proteins are activated by many cytokine receptors to regulate specific gene expression and mitochondrial functions. Their role in cancer is largely context-dependent as they can both act as oncogenes and tumor suppressors. We review here the role of STAT3/5 activation in solid cancers and summarize their association with survival in cancer patients. The molecular mechanisms that underpin the oncogenic activity of STAT3/5 signaling include the regulation of genes that control cell cycle and cell death. However, recent advances also highlight the critical role of STAT3/5 target genes mediating inflammation and stemness. In addition, STAT3 mitochondrial functions are required for transformation. On the other hand, several tumor suppressor pathways act on or are activated by STAT3/5 signaling, including tyrosine phosphatases, the sumo ligase Protein Inhibitor of Activated STAT3 (PIAS3), the E3 ubiquitin ligase TATA Element Modulatory Factor/Androgen Receptor-Coactivator of 160 kDa (TMF/ARA160), the miRNAs miR-124 and miR-1181, the Protein of alternative reading frame 19 (p19ARF)/p53 pathway and the Suppressor of Cytokine Signaling 1 and 3 (SOCS1/3) proteins. Cancer mutations and epigenetic alterations may alter the balance between pro-oncogenic and tumor suppressor activities associated with STAT3/5 signaling, explaining their context-dependent association with tumor progression both in human cancers and animal models.

Sphingosine 1-phosphate signalling in cancer

2012 ◽  
Vol 40 (1) ◽  
pp. 94-100 ◽  
Author(s):  
Nigel J. Pyne ◽  
Francesca Tonelli ◽  
Keng Gat Lim ◽  
Jaclyn S. Long ◽  
Joanne Edwards ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Sphingosine Kinase ◽  
Receptor Expression ◽  
Sphingosine Kinase 1 ◽  
Histone Deacetylase 1 ◽  
S1p Receptors ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor

There is an increasing body of evidence demonstrating a critical role for the bioactive lipid S1P (sphingosine 1-phosphate) in cancer. S1P is synthesized and metabolized by a number of enzymes, including sphingosine kinase, S1P lyase and S1P phosphatases. S1P binds to cell-surface G-protein-coupled receptors (S1P1–S1P5) to elicit cell responses and can also regulate, by direct binding, a number of intracellular targets such as HDAC (histone deacetylase) 1/2 to induce epigenetic regulation. S1P is involved in cancer progression including cell transformation/oncogenesis, cell survival/apoptosis, cell migration/metastasis and tumour microenvironment neovascularization. In the present paper, we describe our research findings regarding the correlation of sphingosine kinase 1 and S1P receptor expression in tumours with clinical outcome and we define some of the molecular mechanisms underlying the involvement of sphingosine kinase 1 and S1P receptors in the formation of a cancer cell migratory phenotype. The role of sphingosine kinase 1 in the acquisition of chemotherapeutic resistance and the interaction of S1P receptors with oncogenes such as HER2 is also reviewed. We also discuss novel aspects of the use of small-molecule inhibitors of sphingosine kinase 1 in terms of allosterism, ubiquitin–proteasomal degradation of sphingosine kinase 1 and anticancer activity. Finally, we describe how S1P receptor-modulating agents abrogate S1P receptor–receptor tyrosine kinase interactions, with potential to inhibit growth-factor-dependent cancer progression.

scholarly journals Pulmonary Hypertension Associated With Scleroderma and Connective Tissue Disease: Potential Molecular and Cellular Targets

2017 ◽  
Vol 16 (2) ◽  
pp. 61-67
Author(s):  
Maria Trojanowska
Keyword(s):  
Pulmonary Hypertension ◽  
Connective Tissue ◽  
Connective Tissue Disease ◽  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Connective Tissue Diseases ◽  
Clinical Manifestations ◽  
Response To Treatment ◽  
Organ Systems

Systemic sclerosis (SSc) is characterized by autoimmunity, small-vessel vasculopathy, and fibrosis causing damage in multiple organ systems. Pulmonary arterial hypertension (PAH) is a serious and often fatal complication of SSc, occurring in patients with the limited (lcSSc) and diffuse (dcSSc) forms of the disease and affecting 8% to 15% of patients.12 While pulmonary hypertension associated with connective tissue disease (CTD-PAH) has similar clinical features as idiopathic PAH, 1-year survival and freedom from hospitalization are lower in CTD-PAH.3 SSc-PAH has the worst 1-year survival rate at 82% compared with other connective tissue diseases, including systemic lupus erythematosus, mixed connective tissue disease, and rheumatoid arthritis.34 Despite the recent progress in the development of disease-targeted therapies, patients with SSc-PAH have a poorer response to treatment and a worse prognosis than other subgroups of PAH.1 Autoimmunity and prolonged vasculopathy preceding the development of clinical manifestations of SSc-PAH may play a critical role in the poorer outcome of SSc-PAH patients.1 This article will provide an overview of the recent findings related to cellular and molecular mechanisms associated with the development of PAH, with an emphasis on SSc-PAH.

scholarly journals Post-translational modifications of EZH2 in cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Zhongwei Li ◽  
Minle Li ◽  
Diandian Wang ◽  
Pingfu Hou ◽  
Xintian Chen ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Therapeutic Potential ◽  
Post Translational Modifications ◽  
Polycomb Repressive Complex 2 ◽  
Binding Partners ◽  
Regulate Protein ◽  
Main Component

AbstractEnhancer of zeste homolog 2 (EZH2), as a main component of Polycomb Repressive Complex 2, catalyzes histone H3K27me3 to silence its target gene expression. EZH2 upregulation results in cancer development and poor prognosis of cancer patients. Post-translational modifications (PTMs) are important biological events in cancer progression. PTMs regulate protein conformation and diversity functions. Recently, mounting studies have demonstrated that EZH2 stability, histone methyltransferase activity, localization, and binding partners can be regulated by PTMs, including phosphorylation, O-GlcNAcylation, acetylation, methylation and ubiquitination. However, the detailed molecular mechanisms of the EZH2-PTMs and whether other types of PTMs occur in EZH2 remain largely unclear. This review presents an overview of different roles of EZH2 modification and EZH2-PTMs crosstalk during tumorigenesis and cancer metastasis. We also discussed the therapeutic potential of targeting EZH2 modifications for cancer therapy.

scholarly journals Metastatic suppression by DOC2B is mediated by inhibition of epithelial-mesenchymal transition and induction of senescence

2021 ◽  
Author(s):  
Samatha Bhat ◽  
Divya Adiga ◽  
Vaibhav Shukla ◽  
Kanive Parashiva Guruprasad ◽  
Shama Prasada Kabekkodu ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Vesicle Trafficking ◽  
Critical Role ◽  
Anoikis Resistance ◽  
Mesenchymal Transition ◽  
Intracellular Vesicle

AbstractSenescence induction and epithelial-mesenchymal transition (EMT) events are the opposite sides of the spectrum of cancer phenotypes. The key molecules involved in these processes may get influenced or altered by genetic and epigenetic changes during tumor progression. Double C2-like domain beta (DOC2B), an intracellular vesicle trafficking protein of the double C2 protein family, plays a critical role in exocytosis, neurotransmitter release, and intracellular vesicle trafficking. DOC2B is repressed by DNA promoter hypermethylation and functions as a tumor growth regulator in cervical cancer. To date, the molecular mechanisms of DOC2B in cervical cancer progression and metastasis is elusive. Herein, the biological functions and molecular mechanisms regulated by DOC2B and its impact on senescence and EMT are described. DOC2B inhibition promotes proliferation, growth, and migration by relieving G0/G1-S arrest, actin remodeling, and anoikis resistance in Cal27 cells. It enhanced tumor growth and liver metastasis in nude mice with the concomitant increase in metastasis-associated CD55 and CD61 expression. Inhibition of EMT and promotion of senescence by DOC2B is a calcium-dependent process and accompanied by calcium-mediated interaction between DOC2B and CDH1. In addition, we have identified several EMT and senescence regulators as targets of DOC2B. We show that DOC2B may act as a metastatic suppressor by inhibiting EMT through induction of senescence via DOC2B-calcium-EMT-senescence axis. Graphical abstract

scholarly journals The role of platelets in tumor cell metastasis

2021 ◽  
Vol 20 (4) ◽  
pp. 185-190
Author(s):  
A. A. Yakusheva ◽  
A. A. Filkova
Keyword(s):  
Tumor Cells ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Circulatory System ◽  
Main Function ◽  
Cell Metastasis ◽  
Inflammatory Processes ◽  
Extensive Experimental Data

Platelets are small, nuclear-free cells whose main function is to stop bleeding. In addition to performing a hemostatic function, platelets are also involved in immune and inflammatory processes. Extensive experimental data suggest that platelets support tumor metastasis and their activation plays a critical role in cancer progression. In the circulatory system, platelets protect tumor cells from immune elimination and promote their arrest at the endothelium, supporting the formation of secondary lesions. Due to the significant contribution of platelets to tumor cells survival and propagation, antithrombotic drugs are considered as a novel anti-metastasis approach. In this article, the authors set a goal to summarize and update the currently existing knowledge about the molecular mechanisms and the role of platelets-tumor cells interaction, as well as to discuss the possibility of platelets receptors as anti-metastasis targets. 

scholarly journals Progress of Research on Diffuse Axonal Injury after Traumatic Brain Injury

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Junwei Ma ◽  
Kai Zhang ◽  
Zhimin Wang ◽  
Gang Chen
Keyword(s):  
Protein Transport ◽  
Calcium Influx ◽  
Critical Role ◽  
Diffuse Axonal Injury ◽  
Transport Proteins ◽  
Clear Understanding ◽  
Structural Protein ◽  
Pathological Mechanism ◽  
Hydrolysis Of

The current work reviews the concept, pathological mechanism, and process of diagnosing of DAI. The pathological mechanism underlying DAI is complicated, including axonal breakage caused by axonal retraction balls, discontinued protein transport along the axonal axis, calcium influx, and calpain-mediated hydrolysis of structural protein, degradation of axonal cytoskeleton network, the changes of transport proteins such as amyloid precursor protein, and changes of glia cells. Based on the above pathological mechanism, the diagnosis of DAI is usually made using methods such as CT, traditional and new MRI, biochemical markers, and neuropsychological assessment. This review provides a basis in literature for further investigation and discusses the pathological mechanism. It may also facilitate improvement of the accuracy of diagnosis for DAI, which may come to play a critical role in breaking through the bottleneck of the clinical treatment of DAI and improving the survival and quality of life of patients through clear understanding of pathological mechanisms and accurate diagnosis.

scholarly journals Regulation of Deubiquitinating Enzymes by Post-Translational Modifications

2020 ◽  
Vol 21 (11) ◽  
pp. 4028 ◽  
Author(s):  
Tanuza Das ◽  
Sang Chul Shin ◽  
Eun Joo Song ◽  
Eunice EunKyeong Kim
Keyword(s):  
Catalytic Activity ◽  
Posttranslational Modifications ◽  
Critical Role ◽  
Clear Understanding ◽  
Deubiquitinating Enzymes ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Multiple Factors ◽  
Regulatory Processes ◽  
Partner Proteins

Ubiquitination and deubiquitination play a critical role in all aspects of cellular processes, and the enzymes involved are tightly regulated by multiple factors including posttranslational modifications like most other proteins. Dysfunction or misregulation of these enzymes could have dramatic physiological consequences, sometimes leading to diseases. Therefore, it is important to have a clear understanding of these regulatory processes. Here, we have reviewed the posttranslational modifications of deubiquitinating enzymes and their consequences on the catalytic activity, stability, abundance, localization, and interaction with the partner proteins.

scholarly journals SATB1 enhances gastric cancer progression and metastasis via upregulation of CLIP4/DZIP1/ PRICKLE2 axis in gastric cancer patients

2021 ◽  
Vol 26 (6) ◽  
pp. 3062-3073
Author(s):  
SAMINA GUL ◽  
AMJAD ALI ◽  
SHAHZAD AHMAD ◽  
CHONGYI ZHAO ◽  
ASAD ALI SHAH ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Survival Rates ◽  
Signaling Axis ◽  
Satb1 Expression ◽  
Gastric Cancer Patients ◽  
Cancer Bioinformatics

SATB1 (Special AT-rich sequence binding protein 1) plays key role in chromatin remodeling and geneexpression. SATB1 has been shown to promote invasion, migration and metastasis. However, the underlying molecular mechanisms, function and clinicopathological features of SATB1 in gastric cancer (GC) remains poorly understood. Here, we show that SATB1 plays critical role in GC progression. SATB1 upregulates in GC patients’ samples and shows co-apmlification with a subset of oncogenic proteins (PRICKLE2, ZEB1, CBWX7, WWTR1, ENAH, DZIP1, IGSF11, ZSCAN18, GFRA2, GFRA1, FGFR1, HDAC4, GHR, TIMP3, CLIP4, TAGLN and ILK) in different subtypes of GC. SATB1 shows positive correlation with GC promoting oncogenes and enhances the expression of metastasis associated genes in GC samples to potentiate GC progression. SATB1 enhances WNT/NOTCH signaling axis in GC samples. In contrast, STAB1 suppresses a network of tumor suppressor genes in GC samples. Moreover, SATB1 expression negatively correlates with GC patient’s survival. Importantly, we found that SATB1 co-amplified genes CLIP4, DZIP1 and PRICKLE2 independently involve in GC progression. Overexpression of CLIP4, DZIP1 and PRICKLE2 show poor survival rates in GC patients. DZIP1 empowers AKT3/FGF2/FGFR1 and CXCR3/CXCR6 in GC patients. PRICKLE2 enhances GC progression by targeting FGFR1/NOTCH3/WNT4 signaling. Taken together, these results identified novel roles of SATB1, CLIP4, DZIP1 and PRICKLE2 in the GC invasion, migration and metastasis using cancer bioinformatics approach. These results highlights clinical significance of SATB1, CLIP4, DZIP1 and PRICKLE2 in GC patients and furthermore, these proteins may serve as prognostic markers in GC. These results also provide SATB1, CLIP4, DZIP1 and PRICKLE2 as potential chemotherapeutic targets in treatment of gastric cancer patients.

scholarly journals Circular RNA circLOC101928570 Suppress Systemic Lupus Erythematosus Progression Via Targeting the miR-150/c-myb Axis

2021 ◽  
Author(s):  
Xingwang Zhao ◽  
Longlong Zhang ◽  
Juan Wang ◽  
Zhiqiang Song ◽  
Bing Ni ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Luciferase Reporter ◽  
Enzyme Linked Immunosorbent Assay ◽  
Transcriptional Level ◽  
Systemic Lupus ◽  
Potential Biomarker ◽  
Repressive Effect

Abstract Background: Accumulating evidence supports the implication of circRNAs in systemic lupus erythematosus (SLE). however, little is known about their the detailed mechanisms and the roles of circRNAs in the pathogenesis of SLE.Methods: Quantitative real time-PCR (qRT-PCR) was used to determine the levels of circLOC101928570 and miR-150 in peripheral blood mononuclear cells (PBMCs) of SLE. Overexpression and knockdown experiments were conducted to assess the effects of circLOC101928570. Fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP), luciferase reporter assays, western blot, flow cytometry analysis and enzyme-linked immunosorbent assay (ELISA) were used to investigate the molecular mechanisms underlying the function of circLOC101928570. Results: The results showed that the level of circLOC101928570 was significantly down-regulated in SLE and correlated with systemic lupus erythematosus disease activity index (SLEDAI). Functionally, circLOC101928570 acted as a miR-150 sponge to relieve the repressive effect on its target c-myb, which modulates the activation of immune inflammatory responses. CircLOC101928570 knockdown enhanced apoptosis. Moreover, circLOC101928570 promote the transcriptional level of IL2RA through directly regulate miR-150/c-myb axis. Conclusion: Overall, our findings demonstrated that circLOC101928570 played a critical role in SLE. The down-expression of circLOC101928570 suppressed SLE progression through miR-150/c-myb/IL2RA axis. Our findings identified that circLOC101928570 serve as a potential biomarker for the diagnosis and therapy of SLE.

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