scholarly journals Multifaceted Functional Role of Semaphorins in Glioblastoma

2019 ◽  
Vol 20 (9) ◽  
pp. 2144 ◽  
Author(s):  
Cristiana Angelucci ◽  
Gina Lama ◽  
Gigliola Sica
Keyword(s):  
Axon Guidance ◽  
Treatment Options ◽  
Migration And Invasion ◽  
Tumor Type ◽  
Metastatic Progression ◽  
Oncogenic Pathways ◽  
Membrane Bound ◽  
Wide Group

Glioblastoma (GBM) is the most malignant tumor type affecting the adult central nervous system. Despite advances in therapy, the prognosis for patients with GBM remains poor, with a median survival of about 15 months. To date, few treatment options are available and recent trials based on the molecular targeting of some of the GBM hallmark pathways (e.g., angiogenesis) have not produced any significant improvement in overall survival. The urgent need to develop more efficacious targeted therapies has led to a better molecular characterization of GBM, revealing an emerging role of semaphorins in GBM progression. Semphorins are a wide group of membrane-bound and secreted proteins, originally identified as axon guidance cues, signaling through their receptors, neuropilins, and plexins. A number of semaphorin signals involved in the control of axonal growth and navigation during development have been found to furthermore participate in crosstalk with different dysfunctional GBM pathways, controlling tumor cell proliferation, migration, and invasion, as well as tumor angiogenesis or immune response. In this review, we summarize the regulatory activities mediated by semaphorins and their receptors on the oncogenic pathways implicated in GBM growth and invasive/metastatic progression.

scholarly journals SMYD3: An Oncogenic Driver Targeting Epigenetic Regulation and Signaling Pathways

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 142 ◽  
Author(s):  
Cinzia Bottino ◽  
Alessia Peserico ◽  
Cristiano Simone ◽  
Giuseppina Caretti
Keyword(s):  
Signaling Pathways ◽  
Cancer Progression ◽  
Transcriptional Response ◽  
Migration And Invasion ◽  
Transcriptional Reprogramming ◽  
Oncogenic Pathways ◽  
Tumor Transformation ◽  
Cancer Types ◽  
Oncogenic Driver

SMYD3 is a member of the SMYD lysine methylase family and plays an important role in the methylation of various histone and non-histone targets. Aberrant SMYD3 expression contributes to carcinogenesis and SMYD3 upregulation was proposed as a prognostic marker in various solid cancers. Here we summarize SMYD3-mediated regulatory mechanisms, which are implicated in the pathophysiology of cancer, as drivers of distinct oncogenic pathways. We describe SMYD3-dependent mechanisms affecting cancer progression, highlighting SMYD3 interplay with proteins and RNAs involved in the regulation of cancer cell proliferation, migration and invasion. We also address the effectiveness and mechanisms of action for the currently available SMYD3 inhibitors. The findings analyzed herein demonstrate that a complex network of SMYD3-mediated cytoplasmic and nuclear interactions promote oncogenesis across different cancer types. These evidences depict SMYD3 as a modulator of the transcriptional response and of key signaling pathways, orchestrating multiple oncogenic inputs and ultimately, promoting transcriptional reprogramming and tumor transformation. Further insights into the oncogenic role of SMYD3 and its targeting of different synergistic oncogenic signals may be beneficial for effective cancer treatment.

Biochemistry and site-directed mutational analysis of Δ7-sterol-C5(6)-desaturase

2000 ◽  
Vol 28 (6) ◽  
pp. 799-803 ◽  
Author(s):  
A. Rahier ◽  
P. Benveniste ◽  
T. Husselstein ◽  
M. Taton
Keyword(s):  
Biochemical Characterization ◽  
Mutational Analysis ◽  
Enzyme System ◽  
Conserved Residues ◽  
Catalytic Role ◽  
Membrane Bound ◽  
Haem Iron ◽  
Oxygen Site

This report describes recent work on the process of desaturation at C5(6) of sterol precursors in plants. Biochemical characterization of the plant Δ7-sterol C5(6)-desaturase (5-DES) indicates that the enzyme system involved shows important similarities to the soluble and membrane-bound non-haem iron desaturases found in eukaryotes, including cyanide and hydrophobic chelators sensitivity, CO resistance and a requirement for exogenous reductant and molecular oxygen. Site-directed mutational analysis of highly conserved residues in 5-DES indicated that eight histidine residues from three histidine-rich motifs were essential for the catalysis, possibly by providing the ligands for a putative Fe centre. This mutational analysis also revealed the catalytic role of the functionally conserved Thr-114.

scholarly journals Functional Characterization of the IlpA Protein of Vibrio vulnificus as an Adhesin and Its Role in Bacterial Pathogenesis

2010 ◽  
Vol 78 (6) ◽  
pp. 2408-2417 ◽  
Author(s):  
Kyung-Jo Lee ◽  
Na Yeon Lee ◽  
Yang-Soo Han ◽  
Juri Kim ◽  
Kyu-Ho Lee ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Vibrio Vulnificus ◽  
Polyclonal Antibodies ◽  
Functional Characterization ◽  
Intestinal Epithelial ◽  
Human Intestinal Epithelial Cells ◽  
Direct Binding ◽  
Membrane Bound

ABSTRACT Vibrio vulnificus is a Gram-negative bacterium that causes a fatal septicemia. One of its virulence factors is a membrane-bound lipoprotein, IlpA, which can induce cytokine production in human immune cells. In the present study, the role of IlpA as an adhesion molecule was investigated. An ilpA-deleted V. vulnificus mutant showed significantly decreased adherence to INT-407 human intestinal epithelial cells, which in turn resulted in reduced cytotoxicity. The ΔilpA mutant recovered the adherence ability of the wild type by complementation in trans with the intact ilpA gene. In addition, pretreatment of V. vulnificus with anti-IlpA polyclonal antibodies resulted in a significant reduction of bacterial adherence. To localize the domain of IlpA required for cytoadherence, three truncated recombinant IlpA polypeptides were constructed and tested for the ability to adhere to human cells by a ligand-binding immunoblot assay and fluorescence microscopy. The polypeptide containing the carboxy (C)-terminal hydrophilic domain exhibited direct binding to INT-407 cells. Therefore, the C-terminal domain of IlpA allows this protein to be an adhesion molecule of V. vulnificus.

scholarly journals Functional Characterization of Colon-Cancer-Associated Variants in ADAM17 Affecting the Catalytic Domain

Biomedicines ◽  
2020 ◽  
Vol 8 (11) ◽  
pp. 463
Author(s):  
Jan Philipp Dobert ◽  
Anne-Sophie Cabron ◽  
Philipp Arnold ◽  
Egor Pavlenko ◽  
Stefan Rose-John ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Functional Characterization ◽  
Tumor Development ◽  
Point Mutations ◽  
Modern World ◽  
Protective Effects ◽  
Tissue Samples ◽  
Membrane Bound

Although extensively investigated, cancer is still one of the most devastating and lethal diseases in the modern world. Among different types, colorectal cancer (CRC) is most prevalent and mortal, making it an important subject of research. The metalloprotease ADAM17 has been implicated in the development of CRC due to its involvement in signaling pathways related to inflammation and cell proliferation. ADAM17 is capable of releasing membrane-bound proteins from the cell surface in a process called shedding. A deficiency of ADAM17 activity has been previously shown to have protective effects against CRC in mice, while an upregulation of ADAM17 activity is suspected to facilitate tumor development. In this study, we characterize ADAM17 variants found in tissue samples of cancer patients in overexpression studies. We here focus on point mutations identified within the catalytic domain of ADAM17 and could show a functional dysregulation of the CRC-associated variants. Since the catalytic domain of ADAM17 is the only region structurally determined by crystallography, we study the effect of each point mutation not only to learn more about the role of ADAM17 in cancer, but also to investigate the structure–function relationships of the metalloprotease.

scholarly journals Biosynthesis of mycobacterial methylmannose polysaccharides requires a unique 1-O-methyltransferase specific for 3-O-methylated mannosides

2019 ◽  
Vol 116 (3) ◽  
pp. 835-844 ◽  
Author(s):  
Jorge Ripoll-Rozada ◽  
Mafalda Costa ◽  
José A. Manso ◽  
Ana Maranha ◽  
Vanessa Miranda ◽  
...  
Keyword(s):  
Cell Envelope ◽  
3D Structure ◽  
Host Immune System ◽  
Opportunistic Pathogens ◽  
Docking Simulations ◽  
Optimal Function ◽  
Wide Group ◽  
Identification And Characterization

Mycobacteria are a wide group of organisms that includes strict pathogens, such as Mycobacterium tuberculosis, as well as environmental species known as nontuberculous mycobacteria (NTM), some of which—namely Mycobacterium avium—are important opportunistic pathogens. In addition to a distinctive cell envelope mediating critical interactions with the host immune system and largely responsible for their formidable resistance to antimicrobials, mycobacteria synthesize rare intracellular polymethylated polysaccharides implicated in the modulation of fatty acid metabolism, thus critical players in cell envelope assembly. These are the 6-O-methylglucose lipopolysaccharides (MGLP) ubiquitously detected across the Mycobacterium genus, and the 3-O-methylmannose polysaccharides (MMP) identified only in NTM. The polymethylated nature of these polysaccharides renders the intervening methyltransferases essential for their optimal function. Although the knowledge of MGLP biogenesis is greater than that of MMP biosynthesis, the methyltransferases of both pathways remain uncharacterized. Here, we report the identification and characterization of a unique S-adenosyl-l-methionine–dependent sugar 1-O-methyltransferase (MeT1) from Mycobacterium hassiacum that specifically blocks the 1-OH position of 3,3′-di-O-methyl-4α-mannobiose, a probable early precursor of MMP, which we chemically synthesized. The high-resolution 3D structure of MeT1 in complex with its exhausted cofactor, S-adenosyl-l-homocysteine, together with mutagenesis studies and molecular docking simulations, unveiled the enzyme’s reaction mechanism. The functional and structural properties of this unique sugar methyltransferase further our knowledge of MMP biosynthesis and provide important tools to dissect the role of MMP in NTM physiology and resilience.

scholarly journals Partial purification and characterization of a peroxidase activity from human placenta

1990 ◽  
Vol 268 (3) ◽  
pp. 739-743 ◽  
Author(s):  
J L Nelson ◽  
A P Kulkarni
Keyword(s):  
Peroxidase Activity ◽  
Potential Role ◽  
Gel Filtration ◽  
Partial Purification ◽  
Human Haemoglobin ◽  
Prostaglandin Synthase ◽  
Membrane Bound ◽  
Cytochrome P 450

Peroxidases can metabolize a variety of xenobiotics to reactive intermediates capable of binding to protein or DNA. The potential role of these enzymes in fetotoxicity has not been explored. In this study, the presence of peroxidase activity was observed in human term and pre-term placenta. Human term placental peroxidase activity (HTPP) was partially purified by concanavalin A affinity chromatography from CaCl2 extracts of the particulate fraction. HTPP appears to be a membrane-bound glycoprotein. Arachidonic acid-dependent oxidation of guaiacol was not observed, suggesting that the peroxidase activity was not due to prostaglandin synthase. Moreover, HTPP preparations were devoid of catalase and spectrally dissimilar from human haemoglobin, cytochrome P-450, eosinophil peroxidase and myloperoxidase, suggesting an endogenous origin. An Mr of approx. 119,000 was determined for HTPP by gel filtration. Cathodic slab-PAGE of cetyltrialkylammonium bromide-solubilized HTPP yielded two peroxidase-staining bands.

scholarly journals Olig2 regulates p53-mediated apoptosis, migration and invasion of melanoma cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ji Eun Lee ◽  
Sungjin Ahn ◽  
Haengdueng Jeong ◽  
Seungchan An ◽  
Cheol Hwan Myung ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Enzyme Activity ◽  
Malignant Cell ◽  
Melanoma Cells ◽  
Migration And Invasion ◽  
High Recurrence Rate ◽  
Metastatic Progression ◽  
Helix Loop Helix ◽  
The Central Nervous System

AbstractMelanoma is a disease with a high recurrence rate and poor prognosis; therefore, the need for targeted therapeutics is steadily increasing. Oligodendrocyte transcription factor2 (Olig2) is a basic helix-loop-helix transcription factor that is expressed in the central nervous system during embryonic development. Olig2 is overexpressed in various malignant cell lines such as lung carcinoma, glioma and melanoma. Olig2 is known as a key transcription factor that promotes tumor growth in malignant glioma. However, the role of Olig2 in melanoma is not well characterized. We analyzed the role of Olig2 in apoptosis, migration, and invasion of melanoma cells. We confirmed that Olig2 was overexpressed in melanoma cells and tissues. Reduction of Olig2 increased apoptosis in melanoma cells by increasing p53 level and caspase-3/-7 enzyme activity. In addition, downregulation of Olig2 suppressed migration and invasion of melanoma cells by inhibiting EMT. Reduction of Olig2 inhibited expression of MMP-1 and the enzyme activity of MMP-2/-9 induced by TGF-β. Moreover, Olig2 was involved in the downstream stages of MEK/ERK and PI3K/AKT, which are major signaling pathways in metastatic progression of melanoma. In conclusion, this study demonstrated the crucial roles of Olig2 in apoptosis, migration, and invasion of melanoma and may help to further our understanding of the relationship between Olig2 and melanoma progression.

scholarly journals The pathophysiology of sepsis—2021 update: Part 1, immunology and coagulopathy leading to endothelial injury

2021 ◽  
Author(s):  
Judith Jacobi
Keyword(s):  
Treatment Options ◽  
Endothelial Injury ◽  
Coagulation Cascade ◽  
Secondary Infections ◽  
Sepsis And Septic Shock ◽  
Risk And Benefit ◽  
Insight Into ◽  
Related Mortality

Abstract Disclaimer In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose To provide an overview of current literature on the pathophysiology of sepsis, with a focus on mediators of endothelial injury and organ dysfunction. Summary Sepsis is a dysregulated response to infection that triggers cascades of interconnected systems. Sepsis has been a significant cause of mortality worldwide, and the recent viral pandemic that may produce severe sepsis and septic shock has been a major contributor to sepsis-related mortality. Understanding of the pathophysiology of sepsis has changed dramatically over the last several decades. Significant insight into the components of the inflammatory response that contribute to endothelial injury and trigger coagulation pathways has been achieved. Similarly, characterization of anti-inflammatory pathways that may lead to secondary infections and poor outcome has illustrated opportunities for improved therapies. Description of an increasing number of important mediators and pathways has occurred and may point the way to novel therapies to address immune dysregulation. Pharmacists will need a fundamental understanding of the overlapping pathways of the immune response to fully prepare for use of novel treatment options. While pharmacists typically understand coagulation cascade how to utilize anticoagulants, the issues in sepsis related coagulopathy and role of mediators such as cytokines and complement and role of activated platelets and neutrophils require a different perspective. Conclusion Pharmacists can benefit from understanding both the cellular and organ system issues in sepsis to facilitate assessment of potential therapies for risk and benefit.

STAT3 and AKT signaling pathways mediate oncogenic role of NRSF in hepatocellular carcinoma

2020 ◽  
Vol 52 (10) ◽  
pp. 1063-1070
Author(s):  
Ming Ma ◽  
Yunhe Zhou ◽  
Ruilin Sun ◽  
Jiahao Shi ◽  
Yutong Tan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathways ◽  
Zinc Finger Protein ◽  
Akt Signaling ◽  
Nervous System Development ◽  
Migration And Invasion ◽  
Tumor Type ◽  
Dependent Manner ◽  
Rnai Technology

Abstract Neuron-restrictive silencer factor (NRSF) is a zinc finger protein that acts as a negative transcriptional regulator by recruiting histone deacetylases and other co-factors. It plays a crucial role in nervous system development and is recently reported to be involved in tumorigenesis in a tumor type-dependent manner; however, the role of NRSF in hepatocellular carcinoma (HCC) tumorigenesis remains unclear. Here, we found that NRSF expression was up-regulated in 27 of 49 human HCC tissue samples examined. Additionally, mice with conditional NRSF-knockout in the liver exhibited a higher tolerance against diethylnitrosamine (DEN)-induced acute liver injury and were less sensitive to DEN-induced HCC initiation. Our results showed that silencing NRSF in HepG2 cells using RNAi technology significantly inhibited HepG2 cell proliferation and severely hindered their migration and invasion potentials. Our results demonstrated that NRSF plays a pivotal role in promoting DEN-induced HCC initiation via a mechanism related to the STAT3 and AKT signaling pathways. Thus, NRSF could be a potential therapeutic target for treating human HCC.

scholarly journals Characterization of the Role of a Non-GPCR Membrane-Bound CFEM Protein in the Pathogenicity and Germination of Botrytis cinerea

2020 ◽  
Vol 8 (7) ◽  
pp. 1043
Author(s):  
Gulab Chand Arya ◽  
Dhruv Aditya Srivastava ◽  
Eswari P. J. Pandaranayaka ◽  
Ekaterina Manasherova ◽  
Dov Bernard Prusky ◽  
...  
Keyword(s):  
Botrytis Cinerea ◽  
Pathogenic Fungi ◽  
Phytopathogenic Fungi ◽  
Fungal Virulence ◽  
Wide Range ◽  
Membrane Bound ◽  
The Common ◽  
G Protein Coupled

The necrotrophic fungus Botrytis cinerea, is considered a major cause of postharvest losses in a wide range of crops. The common fungal extracellular membrane protein (CFEM), containing a conserved eight-cysteine pattern, was found exclusively in fungi. Previous studies in phytopathogenic fungi have demonstrated the role of membrane-bound and secreted CFEM-containing proteins in different aspects of fungal virulence. However, non-G protein-coupled receptor (non-GPCR) membrane CFEM proteins have not been studied yet in phytopathogenic fungi. In the present study, we have identified a non-GPCR membrane-bound CFEM-containing protein, Bcin07g03260, in the B. cinerea genome, and generated deletion mutants, ΔCFEM-Bcin07g03260, to study its potential role in physiology and virulence. Three independent ΔCFEM-Bcin07g03260 mutants showed significantly reduced progression of a necrotic lesion on tomato (Solanum lycopersicum) leaves. Further analysis of the mutants revealed significant reduction (approximately 20–30%) in conidial germination and consequent germ tube elongation compared with the WT. Our data complements a previous study of secreted ΔCFEM1 mutants of B. cinerea that showed reduced progression of necrotic lesions on leaves, without effect on germination. Considering various functions identified for CFEM proteins in fungal virulence, our work illustrates a potential new role for a non-GPCR membrane CFEM in pathogenic fungi to control virulence in the fungus B. cinerea.

Sign in / Sign up

Export Citation Format

Share Document