scholarly journals Evaluation of the Anti-Tumor Activity of Small Molecules Targeting Eph/Ephrins in APC min/J Mice

2020 ◽  
Vol 13 (4) ◽  
pp. 69
Author(s):  
Miriam Corrado ◽  
Carmine Giorgio ◽  
Elisabetta Barocelli ◽  
Giuseppe Vittucci Marzetti ◽  
Anna Maria Cantoni ◽  
...  
Keyword(s):  
Small Molecules ◽  
Tyrosine Kinases ◽  
Tumor Development ◽  
Eph Receptors ◽  
Pharmacological Approach ◽  
Ephrin Ligands ◽  
Prevent Tumor Growth ◽  
First Time ◽  
Anti Tumor Activity

The Eph receptors are the largest receptors tyrosine kinases (RTKs) family in humans and together with ephrin ligands constitute a complex cellular communication system often dysregulated in many tumors. The role of the Eph-ephrin system in colorectal cancer (CRC) has been investigated and different expression of Eph receptors have been associated with tumor development and progression. In light of this evidence, we investigated if a pharmacological approach aimed at inhibiting Eph/ephrin interaction through small molecules could prevent tumor growth in APC min/J mice. The 8-week treatment with the Eph-ephrin antagonist UniPR129 significantly reduced the number of adenomas in the ileum and decreased the diameter of adenomas in the same region. Overall our data suggested as UniPR129 could be able to slow down the tumor development in APC min/J mice. These results further confirm literature data about Eph kinases as a new valuable target in the intestinal cancer and for the first time showed the feasibility of the Eph-ephrin inhibition as a useful pharmacological approach against the intestinal tumorigenesis. In conclusion this work paves the way for further studies with Eph-ephrin inhibitors in order to confirm the Eph antagonism as innovative pharmacological approach with preventive benefit in the intestinal tumor development.

A role for the EphA family in the topographic targeting of vomeronasal axons

Development ◽  
2001 ◽  
Vol 128 (6) ◽  
pp. 895-906
Author(s):  
B. Knoll ◽  
K. Zarbalis ◽  
W. Wurst ◽  
U. Drescher
Keyword(s):  
Tyrosine Kinases ◽  
Expression Patterns ◽  
Eph Receptors ◽  
Accessory Olfactory Bulb ◽  
In Vivo Experiments ◽  
Receptor Concentration ◽  
High Ligand

We have investigated the role of the Eph family of receptor tyrosine kinases and their ligands in the establishment of the vomeronasal projection in the mouse. Our data show intriguing differential expression patterns of ephrin-A5 on vomeronasal axons and of EphA6 in the accessory olfactory bulb (AOB), such that axons with high ligand concentration project onto regions of the AOB with high receptor concentration and vice versa. These data suggest a mechanism for development of this projection that is the opposite of the repellent interaction between Eph receptors and ligands observed in other systems. In support of this idea, when given the choice of whether to grow on lanes containing EphA-F(c)/laminin or F(c)/laminin protein (in the stripe assay), vomeronasal axons prefer to grow on EphA-F(c)/laminin. Analysis of ephrin-A5 mutant mice revealed a disturbance of the topographic targeting of vomeronasal axons to the AOB. In summary, these data, which are derived from in vitro and in vivo experiments, indicate an important role of the EphA family in setting up the vomeronasal projection.

scholarly journals Emerging Role of E2F Family in Cancer Stem Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Dan Xie ◽  
Qin Pei ◽  
Jingyuan Li ◽  
Xue Wan ◽  
Ting Ye
Keyword(s):  
Stem Cells ◽  
Drug Resistance ◽  
Cancer Stem Cells ◽  
Tumor Development ◽  
Transcriptional Repressors ◽  
Cellular Processes ◽  
Damage Response ◽  
Prevent Tumor Growth ◽  
Cycle Regulation

The E2F family of transcription factors (E2Fs) consist of eight genes in mammals. These genes encode ten proteins that are usually classified as transcriptional activators or transcriptional repressors. E2Fs are important for many cellular processes, from their canonical role in cell cycle regulation to other roles in angiogenesis, the DNA damage response and apoptosis. A growing body of evidence demonstrates that cancer stem cells (CSCs) are key players in tumor development, metastasis, drug resistance and recurrence. This review focuses on the role of E2Fs in CSCs and notes that many signals can regulate the activities of E2Fs, which in turn can transcriptionally regulate many different targets to contribute to various biological characteristics of CSCs, such as proliferation, self-renewal, metastasis, and drug resistance. Therefore, E2Fs may be promising biomarkers and therapeutic targets associated with CSCs pathologies. Finally, exploring therapeutic strategies for E2Fs may result in disruption of CSCs, which may prevent tumor growth, metastasis, and drug resistance.

scholarly journals Zkscan3 affects erythroblast development by regulating the transcriptional activity of GATA1 and KLF1 in mice

2021 ◽  
Author(s):  
Zixuan Li ◽  
Binjie Sheng ◽  
Tingting Zhang ◽  
Tian Wang ◽  
Dan Chen ◽  
...  
Keyword(s):  
Significant Role ◽  
Knockout Mice ◽  
Transcriptional Activity ◽  
Early Stage ◽  
Quantitative Polymerase Chain Reaction ◽  
Tumor Development ◽  
Rna Seq ◽  
Mice Model ◽  
First Time

AbstractZKSCAN3 encodes a zinc-finger transcription factor that regulates the expression of important genes and plays a significant role in tumor development, pathogenesis, and metastasis. However, its biological functions under normal physiological conditions remain largely unknown. In our previous studies, using flow cytometry, we found that the deletion of Zkscan3 may cause abnormal erythropoiesis. In this study, we found that, in a Zkscan3 knockout mice model, the number of splenic early-stage (basophilic-erythroblasts) and late-stage (chromatophilic-erythroblasts to polychromatophilic-erythroblasts through orthochromatophilic-erythroblasts) erythroblasts increased, whereas the number of late erythroblasts in the bone marrow decreased. Moreover, the phenotype was exacerbated after treating mice with phenylhydrazine (PHZ), which causes severe hemolytic anemia. In the knockout mice treated with PHZ, the percentage of reticulocyte in the peripheral blood conspicuously increased, whereas MCHC and red blood cells decreased. Then, we performed RNA-seq and quantitative-polymerase chain reaction assay and found that the expression of GATA1 and Tiam1 in erythroblasts were upregulated, whereas KLF1 was downregulated. Luciferase assays showed that Zkscan3 inhibited the transcription of GATA1 and Tiam1 and promoted the expression of KLF1. Additionally, ChIP and CO-IP results confirmed that Zkscan3 directly interacts with GATA1 and inhibits its transcriptional activity in MEL cells. Our results demonstrate, for the first time, the significant role of Zkscan3 in physiological erythropoiesis through the interaction with GATA1, both at the DNA and protein level, and with Tiam1 and KLF1 at the DNA level.

Eph receptors and ephrins: effectors of morphogenesis

Development ◽  
1999 ◽  
Vol 126 (10) ◽  
pp. 2033-2044 ◽  
Author(s):  
N. Holder ◽  
R. Klein
Keyword(s):  
Cell Migration ◽  
Pattern Formation ◽  
Axon Guidance ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Eph Receptors ◽  
Structural Domains ◽  
Eph Receptor

Eph receptor tyrosine kinases and their ligands, the ephrins, appear to lie functionally at the interface between pattern formation and morphogenesis. We review the role of Eph and ephrin signalling in the formation of segmented structures, in the control of axon guidance and cell migration and in the development of the vasculature. We address the question of how the specificity of response is achieved and discuss the specificity of ephrin-Eph interactions and the significance of structural domains in Eph receptors.

scholarly journals Ephs and Ephrins in Adult Endothelial Biology

2020 ◽  
Vol 21 (16) ◽  
pp. 5623 ◽  
Author(s):  
Dianne Vreeken ◽  
Huayu Zhang ◽  
Anton Jan van Zonneveld ◽  
Janine M. van Gils
Keyword(s):  
Endothelial Cells ◽  
Endothelial Function ◽  
Vascular Development ◽  
Vascular Biology ◽  
Protein Family ◽  
Tissue Homeostasis ◽  
Leukocyte Recruitment ◽  
Eph Receptors ◽  
Ephrin Ligands

Eph receptors and their ephrin ligands are important guidance molecules during neurological and vascular development. In recent years, it has become clear that the Eph protein family remains functional in adult physiology. A subset of Ephs and ephrins is highly expressed by endothelial cells. As endothelial cells form the first barrier between the blood and surrounding tissues, maintenance of a healthy endothelium is crucial for tissue homeostasis. This review gives an overview of the current insights of the role of ephrin ligands and receptors in endothelial function and leukocyte recruitment in the (patho)physiology of adult vascular biology.

scholarly journals The Role of the Eph Receptor Family in Tumorigenesis

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 206
Author(s):  
Meg Anderton ◽  
Emma van der Meulen ◽  
Melissa J. Blumenthal ◽  
Georgia Schäfer
Keyword(s):  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Signalling Pathways ◽  
Cancer Therapies ◽  
Eph Receptors ◽  
Eph Receptor ◽  
Ephrin Ligands ◽  
And Migration ◽  
Receptor Family

The Eph receptor tyrosine kinase family, activated by binding to their cognate ephrin ligands, are important components of signalling pathways involved in animal development. More recently, they have received significant interest due to their involvement in oncogenesis. In most cases, their expression is altered, affecting the likes of cell proliferation and migration. Depending on the context, Eph receptors have the potential to act as both tumour promoters and suppressors in a number of cancers, such as breast cancer, colorectal cancer, lung cancer, prostate cancer, brain cancer and Kaposi’s sarcoma (KS), the latter being intrinsically linked to EphA2 as this is the receptor used for endothelial cell entry by the Kaposi’s sarcoma-associated herpesvirus (KSHV). In addition, EphA2 deregulation is associated with KS, indicating that it has a dual role in this case. Associations between EphA2 sequence variation and KSHV infection/KS progression have been detected, but further work is required to formally establish the links between EphA2 signalling and KS oncogenesis. This review consolidates the available literature of the role of the Eph receptor family, and particularly EphA2, in tumorigenesis, with the aim to develop a better understanding of Eph signalling pathways for potential targeting in novel cancer therapies.

scholarly journals Eph Receptors and Ephrin Ligands: Important Players in Angiogenesis and Tumor Angiogenesis

2010 ◽  
Vol 2010 ◽  
pp. 1-12 ◽  
Author(s):  
Birgit Mosch ◽  
Bettina Reissenweber ◽  
Christin Neuber ◽  
Jens Pietzsch
Keyword(s):  
Tumor Microenvironment ◽  
Embryonic Development ◽  
Tumor Cells ◽  
Recent Work ◽  
Tumor Angiogenesis ◽  
Antiangiogenic Therapy ◽  
Eph Receptors ◽  
Ephrin Ligands

Eph receptors and their ephrin ligands were identified in the late 1980's. Subsequently, they were linked to different physiological and pathophysiological processes like embryonic development, angiogenesis, and tumorigenesis. In this regard, recent work focused on the distribution and effects of Eph receptors and ephrins on tumor cells and tumor microenvironment. The purpose of this review is to outline the role of these molecules in physiological angiogenesis and pathophysiological tumor angiogenesis. Furthermore, novel therapeutical approaches are discussed as Eph receptors and ephrins represent attractive targets for antiangiogenic therapy.

Cross talk between serine/threonine and tyrosine kinases regulates ADP-induced thromboxane generation in platelets

2015 ◽  
Vol 114 (09) ◽  
pp. 558-568 ◽  
Author(s):  
Dheeraj Bhavanasi ◽  
Rachit Badolia ◽  
Bhanu Kanth Manne ◽  
Sumalaxmi Janapati ◽  
Carol Dangelmaier ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Functional Role ◽  
Human Platelets ◽  
Src Family Kinases ◽  
Dependent Manner ◽  
Kinase C ◽  
Pkc Isoforms ◽  
First Time ◽  
Stimulation Of

SummaryADP-induced thromboxane generation depends on Src family kinases (SFKs) and is enhanced with pan-protein kinase C (PKC) inhibitors, but it is not clear how these two events are linked. The aim of the current study is to investigate the role of Y311 phosphorylated PKCδ in regulating ADP-induced platelet activation. In the current study, we employed various inhibitors and murine platelets from mice deficient in specific molecules to evaluate the role of PKCδ in ADP-induced platelet responses. We show that, upon stimulation of platelets with 2MeSADP, Y311 on PKCδ is phosphorylated in a P2Y1/Gq and Lyn-dependent manner. By using PKCδ and Lyn knockout murine platelets, we also show that tyrosine phosphorylated PKCδ plays a functional role in mediating 2MeSADP-induced thromboxane generation. 2MeSADP-induced PKCδ Y311 phosphorylation and thromboxane generation were potentiated in human platelets pre-treated with either a pan-PKC inhibitor, GF109203X or a PKC α/β inhibitor and in PKC α or β knockout murine platelets compared to controls. Furthermore, we show that PKC α/β inhibition potentiates the activity of SFK, which further hyper-phosphorylates PKCδ and potentiates thromboxane generation. These results show for the first time that tyrosine phosphorylated PKCδ regulates ADP-induced thromboxane generation independent of its catalytic activity and that classical PKC isoforms α/β regulate the tyrosine phosphorylation on PKCδ and subsequent thromboxane generation through tyrosine kinase, Lyn, in platelets.

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