scholarly journals microRNAs Biogenesis, Functions and Role in Tumor Angiogenesis

2020 ◽  
Vol 10 ◽  
Author(s):  
Tiziana Annese ◽  
Roberto Tamma ◽  
Michelina De Giorgis ◽  
Domenico Ribatti
Keyword(s):  
Tumor Angiogenesis ◽  
Vasculogenic Mimicry ◽  
Mirna Biogenesis ◽  
Dependent Manner ◽  
Tumor Initiation ◽  
Rna Molecules ◽  
Angiogenic Switch ◽  
Sprouting Angiogenesis ◽  
And Function

microRNAs (miRNAs) are small non-coding RNA molecules, evolutionary conserved. They target more than one mRNAs, thus influencing multiple molecular pathways, but also mRNAs may bind to a variety of miRNAs, either simultaneously or in a context-dependent manner. miRNAs biogenesis, including miRNA transcription, processing by Drosha and Dicer, transportation, RISC biding, and miRNA decay, are finely controlled in space and time.miRNAs are critical regulators in various biological processes, such as differentiation, proliferation, apoptosis, and development in both health and disease. Their dysregulation is involved in tumor initiation and progression. In tumors, they can act as onco-miRNAs or oncosuppressor-miRNA participating in distinct cellular pathways, and the same miRNA can perform both activities depending on the context.In tumor progression, the angiogenic switch is fundamental. miRNAs derived from tumor cells, endothelial cells, and cells of the surrounding microenvironment regulate tumor angiogenesis, acting as pro-angiomiR or anti-angiomiR.In this review, we described miRNA biogenesis and function, and we update the non-classical aspects of them. The most recent role in the nucleus, as transcriptional gene regulators and the different mechanisms by which they could be dysregulated, in tumor initiation and progression, are treated. In particular, we describe the role of miRNAs in sprouting angiogenesis, vessel co-option, and vasculogenic mimicry. The role of miRNAs in lymphoma angiogenesis is also discussed despite the scarcity of data.The information presented in this review reveals the need to do much more to discover the complete miRNA network regulating angiogenesis, not only using high-throughput computational analysis approaches but also morphological ones.

scholarly journals Resistance Mechanisms of Anti-angiogenic Therapy and Exosomes-Mediated Revascularization in Cancer

2020 ◽  
Vol 8 ◽  
Author(s):  
Ye Zeng ◽  
Bingmei M. Fu
Keyword(s):  
Vasculogenic Mimicry ◽  
Resistance Mechanisms ◽  
Vascular Endothelial ◽  
Beneficial Effects ◽  
Sprouting Angiogenesis ◽  
Intussusceptive Angiogenesis ◽  
Angiogenic Therapy ◽  
Tumor Neovascularization ◽  
Endothelial Growth Factor

Anti-angiogenic therapies (AATs) have been widely used for cancer treatment. But the beneficial effects of AATs are short, because AAT-induced tumor revascularization facilitates the tumor relapse. In this mini-review, we described different forms of tumor neovascularization and revascularization including sprouting angiogenesis, vessel co-option, intussusceptive angiogenesis, and vasculogenic mimicry, all of which are closely mediated by vascular endothelial growth factor (VEGF), angiopoietins, matrix metalloproteinases, and exosomes. We also summarized the current findings for the resistance mechanisms of AATs including enhancement in pro-angiogenic cytokines, heterogeneity in tumor-associated endothelial cells (ECs), crosstalk between tumor cells and ECs, masking of extracellular vesicles, matrix stiffness and contributions from fibroblasts, macrophages and adipocytes in the tumor microenvironment. We highlighted the revascularization following AATs, particularly the role of exosome stimulating factors such as hypoxia and miRNA, and that of exosomal cargos such as cytokines, miRNAs, lncRNAs, and circRNAs from the tumor ECs in angiogenesis and revascularization. Finally, we proposed that renormalization of tumor ECs would be a more efficient cancer therapy than the current AATs.

The transmembrane adaptor protein NTAL limits mast cell chemotaxis toward prostaglandin E2

2018 ◽  
Vol 11 (556) ◽  
pp. eaao4354 ◽  
Author(s):  
Ivana Halova ◽  
Monika Bambouskova ◽  
Lubica Draberova ◽  
Viktor Bugajev ◽  
Petr Draber
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Adaptor Protein ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
And Function ◽  
Cell Chemotaxis

Chemotaxis of mast cells is one of the crucial steps in their development and function. Non–T cell activation linker (NTAL) is a transmembrane adaptor protein that inhibits the activation of mast cells and B cells in a phosphorylation-dependent manner. Here, we studied the role of NTAL in the migration of mouse mast cells stimulated by prostaglandin E2 (PGE2). Although PGE2 does not induce the tyrosine phosphorylation of NTAL, unlike IgE immune complex antigens, we found that loss of NTAL increased the chemotaxis of mast cells toward PGE2. Stimulation of mast cells that lacked NTAL with PGE2 enhanced the phosphorylation of AKT and the production of phosphatidylinositol 3,4,5-trisphosphate. In resting NTAL-deficient mast cells, phosphorylation of an inhibitory threonine in ERM family proteins accompanied increased activation of β1-containing integrins, which are features often associated with increased invasiveness in tumors. Rescue experiments indicated that only full-length, wild-type NTAL restored the chemotaxis of NTAL-deficient cells toward PGE2. Together, these data suggest that NTAL is a key inhibitor of mast cell chemotaxis toward PGE2, which may act through the RHOA/ERM/β1-integrin and PI3K/AKT axes.

Viruses Reveal the Secrets of Plasmodesmal Cell Biology

2020 ◽  
Vol 33 (1) ◽  
pp. 26-39 ◽  
Author(s):  
Brandon C. Reagan ◽  
Tessa M. Burch-Smith
Keyword(s):  
Cell Biology ◽  
Plant Viruses ◽  
Rna Molecules ◽  
Obligate Intracellular ◽  
Composition And Structure ◽  
Systemic Spread ◽  
Intercellular Movement ◽  
Virus Research ◽  
And Function

Plasmodesmata (PD) are essential for intercellular trafficking of molecules required for plant life, from small molecules like sugars and ions to macromolecules including proteins and RNA molecules that act as signals to regulate plant development and defense. As obligate intracellular pathogens, plant viruses have evolved to manipulate this communication system to facilitate the initial cell-to-cell and eventual systemic spread in their plant hosts. There has been considerable interest in how viruses manipulate the PD that connect the protoplasts of neighboring cells, and viruses have yielded invaluable tools for probing the structure and function of PD. With recent advances in biochemistry and imaging, we have gained new insights into the composition and structure of PD in the presence and absence of viruses. Here, we first discuss viral strategies for manipulating PD for their intercellular movement and examine how this has shed light on our understanding of native PD function. We then address the controversial role of the cytoskeleton in trafficking to and through PD. Finally, we address how viruses could alter PD structure and consider possible mechanisms of the phenomenon described as ‘gating’. This discussion supports the significance of virus research in elucidating the properties of PD, these persistently enigmatic plant organelles.

scholarly journals OsJAZ13 Negatively Regulates Jasmonate Signaling and Activates Hypersensitive Cell Death Response in Rice

2020 ◽  
Vol 21 (12) ◽  
pp. 4379
Author(s):  
Xiujing Feng ◽  
Lei Zhang ◽  
Xiaoli Wei ◽  
Yun Zhou ◽  
Yan Dai ◽  
...  
Keyword(s):  
Cell Death ◽  
Splice Variants ◽  
Adaptor Protein ◽  
Dependent Manner ◽  
Hypersensitive Cell Death ◽  
Cell Death Response ◽  
Jaz Proteins ◽  
Localization Analysis ◽  
And Function

Jasmonate ZIM-domain (JAZ) proteins belong to the subgroup of TIFY family and act as key regulators of jasmonate (JA) responses in plants. To date, only a few JAZ proteins have been characterized in rice. Here, we report the identification and function of rice OsJAZ13 gene. The gene encodes three different splice variants: OsJAZ13a, OsJAZ13b, and OsJAZ13c. The expression of OsJAZ13 was mainly activated in vegetative tissues and transiently responded to JA and ethylene. Subcellular localization analysis indicated OsJAZ13a is a nuclear protein. Yeast two-hybrid assays revealed OsJAZ13a directly interacts with OsMYC2, and also with OsCOI1, in a COR-dependent manner. Furthermore, OsJAZ13a recruited a general co-repressor OsTPL via an adaptor protein OsNINJA. Remarkably, overexpression of OsJAZ13a resulted in the attenuation of root by methyl JA. Furthermore, OsJAZ13a-overexpressing plants developed lesion mimics in the sheath after approximately 30–45 days of growth. Tillers with necrosis died a few days later. Gene-expression analysis suggested the role of OsJAZ13 in modulating the expression of JA/ethylene response-related genes to regulate growth and activate hypersensitive cell death. Taken together, these observations describe a novel regulatory mechanism in rice and provide the basis for elucidating the function of OsJAZ13 in signal transduction and cell death in plants.

PKCϵ has an alcohol-binding site in its second cysteine-rich regulatory domain

2009 ◽  
Vol 421 (3) ◽  
pp. 405-413 ◽  
Author(s):  
Joydip Das ◽  
Satyabrata Pany ◽  
Ghazi M. Rahman ◽  
Simon J. Slater
Keyword(s):  
Protein Kinase ◽  
Binding Site ◽  
Maximum Effect ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Kinase C ◽  
C1 Domain ◽  
Pkc Protein Kinase C ◽  
And Function

Alcohols regulate the expression and function of PKC (protein kinase C), and it has been proposed that an alcohol-binding site is present in PKCα in its C1 domain, which consists of two cysteine-rich subdomains, C1A and C1B. A PKCϵ-knockout mouse showed a significant decrease in alcohol consumption compared with the wild-type. The aim of the present study was to investigate whether an alcohol-binding site could be present in PKCϵ. Here we show that ethanol inhibited PKCϵ activity in a concentration-dependent manner with an EC50 (equilibrium ligand concentration at half-maximum effect) of 43 mM. Ethanol, butanol and octanol increased the binding affinity of a fluorescent phorbol ester SAPD (sapintoxin-D) to PKCϵC1B in a concentration-dependent manner with EC50 values of 78 mM, 8 mM and 340 μM respectively, suggesting the presence of an allosteric alcohol-binding site in this subdomain. To identify this site, PKCϵC1B was photolabelled with 3-azibutanol and 3-azioctanol and analysed by MS. Whereas azibutanol preferentially labelled His236, Tyr238 was the preferred site for azioctanol. Inspection of the model structure of PKCϵC1B reveals that these residues are 3.46 Å (1 Å=0.1 nm) apart from each other and form a groove where His236 is surface-exposed and Tyr238 is buried inside. When these residues were replaced by alanine, it significantly decreased alcohol binding in terms of both photolabelling and alcohol-induced SAPD binding in the mutant H236A/Y238A. Whereas Tyr238 was labelled in mutant H236A, His236 was labelled in mutant Y238A. The present results provide direct evidence for the presence of an allosteric alcohol-binding site on protein kinase Cϵ and underscore the role of His236 and Tyr238 residues in alcohol binding.

HSP27 Protects Malignant Hematopoietic Cells Against VP-16-Induced Apoptosis through Modulation of P38 and C-JUN.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1276-1276
Author(s):  
Hein Schepers ◽  
Marjan Geugien ◽  
Marco van der Toorn ◽  
Anton L. Bryantsev ◽  
Harm H. Kampinga ◽  
...  
Keyword(s):  
Hematopoietic Cells ◽  
Leukemic Cells ◽  
Dependent Manner ◽  
Apoptosis Pathway ◽  
Hsp27 Expression ◽  
Cd34 Cells ◽  
Induced Apoptosis ◽  
And Function ◽  
Jnk Activation

Abstract In the present study, expression and function of Heat Shock Protein 27 (HSP27) was analyzed in acute myeloid leukemia (AML), since HSP27 expression is linked to unfavourable prognosis. HSP27 protein was predominantly expressed in monocytic blasts (M4-M5, 91%, N = 11) and absent in myeloid leukemic blasts (M1-M2, N = 5). A similar lineage restricted expression was observed in normal hematopoietic cells: high expression in normal CD34+ cells and monocytes, and absent in granulocytes. To study the functional role of HSP27, RNA interference (RNAi) studies were performed in the leukemic TF-1 cell line. These experiments demonstrated a twofold increase in VP-16-induced apoptosis after HSP27 siRNA. In contrast, CD95 Fas-induced apoptosis remained the same, as a result of CD95 Fas-mediated upregulation of HSP27. Additional investigations demonstrated that the increased VP-16-induced apoptosis after HSP27 RNAi, was associated with an enhanced phosphorylation of p38 and c-Jun. This VP-16-induced phosphorylation was subsequently followed by the release of cytochrome c into the cytoplasm, which increased twofold after siRNA treatment. These results indicate that HSP27 plays an important role in the protection against VP-16-induced apoptosis through the modulation of p38 and JNK activation, probably through interference with DAXX-mediated ASK1 activation. This was further underscored by co-immunoprecipitation studies, demonstrating complex formation of DAXX and HSP27 in an ASK1-dependent manner. However, in the investigated AML samples, VP-16-mediated apoptosis correlated moderately with HSP27 expression, although HSP27 was highly expressed and phosphorylated and activated in primitive monocytic AML blasts. This is likely due to the co-expression of p21Waf1/Cip1, which is in the majority of the monocytic AML M4-M5 blasts constitutively localised in the cytoplasm and interferes with apoptosis via the DAXX-ASK1-dependent pathway. Preliminary data indicate that overexpression of a cytoplasmic form of p21 is able to reduce the VP-16-induced apoptosis after RNAi for HSP27 as compared to controls, suggesting a predominant anti-apoptotic role of p21 over HSP27. In summary, we demonstrate a role for HSP27 in the survival of leukemic cells by modulation of the DAXX/p38/JNK apoptosis pathway. This survival advantage can further be promoted by the co-expression of cytoplasmic localised p21Waf1/Cip1 protein, indicating that strategies in AML treatment should be focused on targeting multiple signal transduction pathways.

scholarly journals Loss of Endothelial HIF-Prolyl hydroxylase 2 (PHD2) Induces Cardiac Hypertrophy and Fibrosis

2021 ◽  
Author(s):  
Zhiyu Dai ◽  
Jianding Cheng ◽  
Bin Liu ◽  
Dan Yi ◽  
Anlin Feng ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Left Ventricular ◽  
Dependent Manner ◽  
Adaptive Responses ◽  
Genetic Ablation ◽  
Pathological Cardiac Hypertrophy ◽  
And Function

Cardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial Prolyl-4 hydroxylase 2 (PHD2)/hypoxia inducible factors (HIFs) signaling in the pathogenesis of heart failure remains elusive. We observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Mice with Tie2-Cre-mediated deletion of Egln1 (encoding PHD2) or tamoxifen-induced endothelial Egln1 deletion exhibited left ventricular hypertrophy and cardiac fibrosis. Genetic ablation and pharmacological inhibition of Hif2a but not Hif1a in endothelial Egln1 deficient mice normalized cardiac size and function. The present studies define for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in a HIF-2α dependent manner. Targeting PHD2/HIF-2α signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure.

Role of Myeloid and Other Stromal Cell Types in Tumor Angiogenesis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-32-SCI-32
Author(s):  
Napoleone Ferrara
Keyword(s):  
Growth Factor ◽  
San Francisco ◽  
Tumor Angiogenesis ◽  
Stromal Cell ◽  
Cell Types ◽  
Angiogenic Factor ◽  
Treatment Result ◽  
Angiogenic Switch ◽  
Anti Vegf

Abstract Abstract SCI-32 Role of myeloid and other stromal cell types in tumor angiogenesis Napoleone Ferrara Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA. Vascular endothelial growth factor (VEGF)-A is an important angiogenic factor, involved in both physiological and pathological growth of blood vessels. An anti-VEGF-A monoclonal antibodies and two small molecule VEGF RTK inhibitors have been approved by the FDA for cancer therapy. We have been investigating the mechanisms of refractoriness/resistance to anti-VEGF therapies. Our analysis points to the mobilization and recruitment of CD11b+ Gr1+myeloid cells from the bone marrow in the tumor as key mechanisms for VEGF-independent angiogenesis, at least in mouse models. Tumors that are refractory to anti-VEGF treatment result in increased peripheral mobilization and tumor homing of of CD11b+Gr1+ cells compared to sensitive tumors. Addition of CD11b+Gr1+ cells from resistant tumors was able to sustain the growth of sensitive tumors in the presence of anti-VEGF antibodies. In subsequent studies, we identified the secreted protein Bv8 as a mediator of myeloid cell-dependent angiogenesis. Blocking Bv8 using neutralizing antibodies inhibited the growth of several tumor cell lines transplanted in nude mice and also reduced the angiogenic switch in the RIP-Tag, a transgenic model of insulinoma. The expression of Bv8 by CD11b+ Gr1+myeloid was regulated by hematopoietic growth factor, especially G-CSF. Other studies have implicated tumor-associated fibroblasts as a source of alternative pro-angiogenic factors following VEGF blockade. We identified PDGF-C as one of such mediators. In summary, multiple stromal cell types and signaling pathways may contribute to inherent refractoriness and, potentially, acquired resistance to anti-VEGF therapies in tumors. Disclosures Ferrara: Genentech, Inc.: Employment.

The impact of epigenetics on cardiovascular disease

2020 ◽  
Vol 98 (1) ◽  
pp. 12-22 ◽  
Author(s):  
Dimple Prasher ◽  
Steven C. Greenway ◽  
Raja B. Singh
Keyword(s):  
Cardiac Fibrosis ◽  
Mortality And Morbidity ◽  
Rna Molecules ◽  
Expression Of Genes ◽  
Non Coding Rna ◽  
Novel Biomarkers ◽  
External Risk ◽  
And Function ◽  
The Impact

Mortality and morbidity from cardiovascular diseases (CVDs) represents a huge burden to society. It is recognized that environmental factors and individual lifestyles play important roles in disease susceptibility, but the link between these external risk factors and our genetics has been unclear. However, the discovery of sequence-independent heritable DNA changes (epigenetics) have helped us to explain the link between genes and the environment. Multiple diverse epigenetic processes, including DNA methylation, histone modification, and the expression of non-coding RNA molecules affect the expression of genes that produce important changes in cellular differentiation and function, influencing the health and adaptability of the organism. CVDs such as congenital heart disease, cardiomyopathy, heart failure, cardiac fibrosis, hypertension, and atherosclerosis are now being viewed as much more complex and dynamic disorders. The role of epigenetics in these and other CVDs is currently under intense scrutiny, and we can expect important insights to emerge, including novel biomarkers and new approaches to enable precision medicine. This review summarizes the recent advances in our understanding of the role of epigenetics in CVD.

scholarly journals The role of microRNAs in the legume–Rhizobium nitrogen-fixing symbiosis

2020 ◽  
Vol 71 (5) ◽  
pp. 1668-1680 ◽  
Author(s):  
Nhung T Hoang ◽  
Katalin Tóth ◽  
Gary Stacey
Keyword(s):  
Vascular System ◽  
Regulation Of Gene Expression ◽  
Lotus Japonicus ◽  
Nodule Formation ◽  
Nitrogen Fixing ◽  
Rna Molecules ◽  
Physiological Processes ◽  
Leaf Tissues ◽  
And Function

Abstract Under nitrogen starvation, most legume plants form a nitrogen-fixing symbiosis with Rhizobium bacteria. The bacteria induce the formation of a novel organ called the nodule in which rhizobia reside as intracellular symbionts and convert atmospheric nitrogen into ammonia. During this symbiosis, miRNAs are essential for coordinating the various plant processes required for nodule formation and function. miRNAs are non-coding, endogenous RNA molecules, typically 20–24 nucleotides long, that negatively regulate the expression of their target mRNAs. Some miRNAs can move systemically within plant tissues through the vascular system, which mediates, for example, communication between the stem/leaf tissues and the roots. In this review, we summarize the growing number of miRNAs that function during legume nodulation focusing on two model legumes, Lotus japonicus and Medicago truncatula, and two important legume crops, soybean (Glycine max) and common bean (Phaseolus vulgaris). This regulation impacts a variety of physiological processes including hormone signaling and spatial regulation of gene expression. The role of mobile miRNAs in regulating legume nodule number is also highlighted.

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