FGF signalling in prostate development, tissue homoeostasis and tumorigenesis

2010 ◽  
Vol 30 (5) ◽  
pp. 285-291 ◽  
Author(s):  
Yongshun Lin ◽  
Fen Wang
Keyword(s):  
Tyrosine Kinases ◽  
Developmental Disorders ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Loss Of Function ◽  
Paracrine Factors ◽  
Fgf Receptor ◽  
Prostate Development ◽  
Prostate Carcinogenesis ◽  
Fgf Signalling

The FGFs (fibroblast growth factors) regulate a broad spectrum of biological activities by activating transmembrane FGFR (FGF receptor) tyrosine kinases and their coupled intracellular signalling pathways. In the prostate, the mesenchymal–epithelial interactions mediated by androgen signalling and paracrine factors are essential for gland organogenesis, homoeostasis and tumorigenesis. FGFs mediate these mesenchymal–epithelial interactions in the prostate by paracrinal crosstalk through a diverse set of ligands and receptors. Gain- and loss-of-function studies in mouse models have demonstrated the requirement for the FGF signalling axis in prostate development and homoeostasis. The aberrant induction of this axis in either compartment of the prostate results in developmental disorders, disrupts the homoeostatic balance and leads to prostate carcinogenesis. FGFs are also implicated in mediating androgen signalling in the prostate between mesenchymal and epithelial compartments. Therefore studying FGF signalling in the prostate will help us to better understand the underlying molecular mechanisms by which the gland develops, maintains homoeostasis and undergoes carcinogenesis; as well as yield clues on how androgens mediate these processes and how advanced-tumour prostate cells escape strict androgen regulations.

scholarly journals Lacrimo-Auriculo-Dento-Digital Syndrome Is Caused by Reduced Activity of the Fibroblast Growth Factor 10 (FGF10)-FGF Receptor 2 Signaling Pathway

2007 ◽  
Vol 27 (19) ◽  
pp. 6903-6912 ◽  
Author(s):  
Imad Shams ◽  
Edyta Rohmann ◽  
Veraragavan P. Eswarakumar ◽  
Erin D. Lew ◽  
Satoru Yuzawa ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Fibroblast Growth Factor ◽  
Signaling Pathway ◽  
Biological Activities ◽  
Fibroblast Growth ◽  
Loss Of Function ◽  
Fgf Receptor ◽  
Fibroblast Growth Factor 10 ◽  
Ladd Syndrome

ABSTRACT Lacrimo-auriculo-dento-digital (LADD) syndrome is characterized by abnormalities in lacrimal and salivary glands, in teeth, and in the distal limbs. Genetic studies have implicated heterozygous mutations in fibroblast growth factor 10 (FGF10) and in FGF receptor 2 (FGFR2) in LADD syndrome. However, it is not clear whether LADD syndrome mutations (LADD mutations) are gain- or loss-of-function mutations. In order to reveal the molecular mechanism underlying LADD syndrome, we have compared the biological properties of FGF10 LADD and FGFR2 LADD mutants to the activities of their normal counterparts. These experiments show that the biological activities of three different FGF10 LADD mutants are severely impaired by different mechanisms. Moreover, haploinsufficiency caused by defective FGF10 mutants leads to LADD syndrome. We also demonstrate that the tyrosine kinase activities of FGFR2 LADD mutants expressed in transfected cells are strongly compromised. Since tyrosine kinase activity is stimulated by ligand-induced receptor dimerization, FGFR2 LADD mutants may also exert a dominant inhibitory effect on signaling via wild-type FGFR2 expressed in the same cell. These experiments underscore the importance of signal strength in mediating biological responses and that relatively small changes in receptor signaling may influence the outcome of developmental processes in cells or organs that do not possess redundant signaling pathway.

scholarly journals Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL-12.

1995 ◽  
Vol 181 (1) ◽  
pp. 399-404 ◽  
Author(s):  
C M Bacon ◽  
D W McVicar ◽  
J R Ortaldo ◽  
R C Rees ◽  
J J O'Shea ◽  
...  
Keyword(s):  
T Cells ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Protein Tyrosine Kinases ◽  
Interleukin 12 ◽  
Cell Mediated Immunity ◽  
Receptor Subunit ◽  
Biochemical Basis

Interleukin (IL-12) has many effects on the function of natural killer and T cells, and is important in the control of cell-mediated immunity. IL-2 and IL-12 display many similar activities, yet each also induces a distinct set of responses. A human IL-12 receptor subunit has recently been cloned and, like the IL-2R beta and IL-2R gamma, is a member of the hematopoietic receptor superfamily; however, the molecular mechanisms of IL-12 action are unknown. In this report we show that IL-12 and IL-2 induce tyrosine phosphorylation of distinct members of the Janus (JAK) family of protein tyrosine kinases in human T lymphocytes. IL-12, but not IL-2, stimulates the tyrosine phosphorylation of TYK2 and JAK2, whereas JAK1 and JAK3, which are phosphorylated in response to IL-2, are not phosphorylated after IL-12 treatment. The use of distinct but related JAK family tyrosine kinases by IL-12 and IL-2 may provide a biochemical basis for their different biological activities.

scholarly journals Screening for genes that accelerate the epigenetic ageing clock in humans reveals a role for the H3K36 methyltransferase NSD1

2019 ◽  
Author(s):  
Daniel E. Martin-Herranz ◽  
Erfan Aref-Eshghi ◽  
Marc Jan Bonder ◽  
Thomas M. Stubbs ◽  
Oliver Stegle ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
Molecular Mechanisms ◽  
Ageing Process ◽  
Model Organisms ◽  
Epigenetic Clock ◽  
Sotos Syndrome ◽  
Loss Of Function ◽  
Genomic Context ◽  
Epigenetic Age ◽  
Epigenetic Age Acceleration

ABSTRACTBackgroundEpigenetic clocks are mathematical models that predict the biological age of an individual using DNA methylation data, and which have emerged in the last few years as the most accurate biomarkers of the ageing process. However, little is known about the molecular mechanisms that control the rate of such clocks. Here, we have examined the human epigenetic clock in patients with a variety of developmental disorders, harbouring mutations in proteins of the epigenetic machinery.ResultsUsing the Horvath epigenetic clock, we performed an unbiased screen for epigenetic age acceleration (EAA) in the blood of these patients. We demonstrate that loss-of-function mutations in the H3K36 histone methyltransferase NSD1, which cause Sotos syndrome, substantially accelerate epigenetic ageing. Furthermore, we show that the normal ageing process and Sotos syndrome share methylation changes and the genomic context in which they occur. Finally, we found that the Horvath clock CpG sites are characterised by a higher Shannon methylation entropy when compared with the rest of the genome, which is dramatically decreased in Sotos syndrome patients.ConclusionsThese results suggest that the H3K36 methylation machinery is a key component of theepigenetic maintenance systemin humans, which controls the rate of epigenetic ageing, and this role seems to be conserved in model organisms. Our observations provide novel insights into the mechanisms behind the epigenetic ageing clock and we expect will shed light on the different processes that erode the human epigenetic landscape during ageing.

scholarly journals EPH tyrosine kinase receptors regulate epithelial morphogenesis and phosphorylate the PAR-3 scaffold protein to modulate downstream signaling networks

2020 ◽  
Author(s):  
Sara L. Banerjee ◽  
Noémie Lavoie ◽  
Kévin Jacquet ◽  
Frédéric Lessard ◽  
Josée N. Lavoie ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Cell Communication ◽  
Effector Proteins ◽  
Signaling Networks ◽  
Eph Receptors ◽  
Loss Of Function ◽  
Downstream Signaling ◽  
Cellular Phenotypes ◽  
Regulated Functions

SUMMARYThe EPH family is the largest among receptor tyrosine kinases (RTKs) in humans. In contrast to other RTKs, EPH receptors (EPHRs) cognate ligands, ephrins, are tethered to the cell surface. This results in EPHRs-ephrin signaling being mainly involved in short-range cell-cell communication events that regulate cell adhesion, migration and tissue boundary formation. Although EPHRs functions have been broadly studied, the molecular mechanisms by which they mediate these processes are far from being understood. To address this question, we sought to identify new downstream effector proteins for EPHRs and to determine their requirement for EPHR-regulated functions. To unravel EPHR-associated signaling complexes under native conditions, we applied a mass spectrometry-based approach, namely BioID proximity labeling. We obtained a composite proximity network from EPHA4, -B2, -B3 and -B4 receptors that comprises 395 proteins, most of which were not previously linked to EPH signaling. A gene ontology and pathway term analysis of the most common candidates highlighted cell polarity as a novel function associated with EPHR activity. We found that EPHA1 and EPHB4 expression is restricted to the basal and lateral membrane domains in polarized Caco-2 3D spheroidal cell cultures. We further discovered that their depletion impairs spheroid morphogenesis. In parallel, we examined the contribution of a number of candidates, selected from EPHR proximity networks, via loss-of-function in an EPHR-dependent cell segregation assay. We showed that depletion of the signaling scaffold PAR-3 blocks cell sorting. We also delineated a signalling complex involving C-terminal SRC kinase (CSK), whose recruitment to PAR-3 complexes is dependent on EPHR signals. Our work sheds light on EPHR signaling networks and provides a better understanding of the mechanisms by which EPHRs signal at the membrane to contribute to the establishment of cellular phenotypes.

Synthesis and Biological Activity of Quaternary Quinolinium Salts: A Review

2020 ◽  
Vol 23 (21) ◽  
pp. 2271-2294 ◽  
Author(s):  
Divya Utreja ◽  
Shivali Sharma ◽  
Akhil Goyal ◽  
Komalpreet Kaur ◽  
Sonia Kaushal
Keyword(s):  
Tyrosine Kinases ◽  
Biological Activities ◽  
Polymeric Materials ◽  
Tubulin Polymerization ◽  
Quinoline Derivatives ◽  
Heterocyclic Chemistry ◽  
Biological Profile ◽  
Drug Candidates ◽  
Anti Hiv ◽  
Quinolinium Salts

Heterocyclic chemistry is the only branch of chemistry that has applications in varied areas such as dyes, photosensitizers, coordination compounds, polymeric materials, biological, and many other fields. Quinoline and its derivatives have always engrossed both synthetic chemists and biologists because of their diverse chemical and pharmacological properties as these ring systems can be easily found in various natural products, especially in alkaloids. Among alkaloids, quinoline derivatives i.e. quinolinium salts have attracted much attention nowadays owing to their diverse biological profile such as antimicrobial, antitumor, antifungal, hypotensive, anti-HIV, analgesics and anti-inflammatory, etc. Quinoline and its analogs have recently been examined for their modes of function in the inhibition of tyrosine kinases, proteasome, tubulin polymerization, topoisomerase, and DNA repair. These observations have been guiding scientists for the expansion of new quinoline derivatives with improved and varied biological activities. Quinolinium salts have immense possibilities and scope to investigate these compounds as potential drug candidates. Therefore, we shall present a concise compilation of this work to aid in present knowledge and to help researchers explore an interesting quinoline class having medicinal potential.

Ginger and Heart Health: From Mechanisms to Therapeutics

2020 ◽  
Vol 13 ◽  
Author(s):  
Sajad Fakhri ◽  
Jayanta Kumar Patra ◽  
Swagat Kumar Das ◽  
Gitishree Das ◽  
Mohammad Bagher Majnooni ◽  
...  
Keyword(s):  
Side Effects ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Health Benefits ◽  
Herbal Medicines ◽  
Cardiovascular Complications ◽  
National Database ◽  
Heart Health ◽  
Natural Entities ◽  
Cardioprotective Effects

Background: As a major cause of morbidity and mortality, cardiovascular diseases (CVDs) are globally increasing. In spite of recent development in the management of cardiovascular complications, CVDs have remained a medical challenge. Numerous conventional drugs are used to play cardioprotective roles; however, they are associated with several side effects. Considering the rich phytochemistry and fewer side effects of herbal medicines, they have gained particular attention to develop novel herbal drugs with cardioprotective potentials. Amongst natural entities, ginger is an extensively used and well-known functional food and condiment, possessing plentiful bioactivities, like antiinflammatory, antioxidant, and antimicrobial properties in several disorders management. Objective: The current review deliberated phytochemical properties as well as the ginger/ginger constituents' biological activities and health benefits in several diseases, with particular attention to cardiovascular complications. Methods: A comprehensive research was conducted using multiple databases, including Scopus, PubMed, Medline, Web of Science, national database (Irandoc and SID), and related articles in terms of the health benefits and cardioprotective effects of ginger/ginger constituents. These data were collected from inception until August 2019. Results: In recent years, several herbal medicines were used to develop new drugs with more potency and also minor side effects. Amongst natural entities, ginger is an extensively used traditional medicine in several diseases. The crude extract, along with related pungent active constituents, is mostly attributed to heart health. The cardioprotective effects of ginger are contributed to its cardiotonic, antihypertensive, anti-hyperlipidemia, and anti-platelet effects. The signaling pathways and molecular mechanisms of ginger regarding its cardioprotective effects are also clarified. Conclusion: This study revealed the biological activities, health benefits, and cardioprotective properties of ginger/ginger constituents along with related mechanisms of action, which gave new insights to show new avenue in the treatment of CVDs.

A Comprehensive Review on Pharmacology and Toxicology of Bioactive Compounds of Lagerstroemia Speciosa (L.) Pers.

2020 ◽  
Vol 06 ◽  
Author(s):  
Surya Kant Tripathi ◽  
Sunayna Behera ◽  
Munmun Panda ◽  
Gokhan Zengin ◽  
Bijesh K. Biswal
Keyword(s):  
Molecular Mechanisms ◽  
Biological Activities ◽  
Health Benefit ◽  
Biologically Active ◽  
Pharmacological Properties ◽  
Lagerstroemia Speciosa ◽  
Novel Drugs ◽  
Corosolic Acid ◽  
Current Article ◽  
Preclinical And Clinical Studies

Background: Lagerstroemia speciosa (L.) Pers is one of the most valuable plants due to its ornamental and pharmacological relevance. It is known for its anti-diabetic activity with proved potent blood sugar-lowering activity. The anti-diabetic activity is due to presence of its biologically active component corosolic acid. Moreover, L. speciosa and its novel purified compounds are also well-known for its several biological activities with beneficial health benefit on the human being. Objectives: This review provides a summary of pharmacokinetics, toxicity, and pharmacological properties of L. speciosa and its purified phytochemicals which may help researchers for building up new researches in near future. Methods: The current article is prepared by collecting through various online and offline databases. Preliminary source of study and data collection for outlining the review was research articles and reviews that have been already published by many reputed publishers, including Springer, Elsevier, Taylor & Francis imprints, BMC, Willy, The Norwegian Academy of Science and Letters, Environmental health prospective (EHP), and PLOS One. Result: The available studies results suggested that the L. speciosa and its phytochemicals showed antidiabetic, anticancer, anti-inflammatory, antimicrobial, antioxidant, antiviral, anti-obesity, and cardio-protective activities. Pharmacokinetic stud-ies suggested the low bioavailability of its purified compounds. However, nano-encapsulation can improve the bioavaila-bility related issue and effectively potentiate the medicinal properties of its constituents. Conclusion: Considering the worthy pharmacological properties, L. speciosa is considered as a potent source of several novel drugs. Though, still preclinical and clinical studies are needed to reveal the targets, molecular mechanisms, bioavail-ability, and toxicity of its constituents.

scholarly journals Circular RNA mmu_circ_0005019 inhibits fibrosis of cardiac fibroblasts and reverses electrical remodeling of cardiomyocytes

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Na Wu ◽  
Chengying Li ◽  
Bin Xu ◽  
Ying Xiang ◽  
Xiaoyue Jia ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cardiac Fibroblasts ◽  
Circular Rna ◽  
Protective Role ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
Candidate Target ◽  
Paired Control ◽  
Reporter Assays ◽  
And Migration

Abstract Background Circular RNA (circRNA) have been reported to play important roles in cardiovascular diseases including myocardial infarction and heart failure. However, the role of circRNA in atrial fibrillation (AF) has rarely been investigated. We recently found a circRNA hsa_circ_0099734 was significantly differentially expressed in the AF patients atrial tissues compared to paired control. We aim to investigate the functional role and molecular mechanisms of mmu_circ_0005019 which is the homologous circRNA in mice of hsa_circ_0099734 in AF. Methods In order to investigate the effect of mmu_circ_0005019 on the proliferation, migration, differentiation into myofibroblasts and expression of collagen of cardiac fibroblasts, and the effect of mmu_circ_0005019 on the apoptosis and expression of Ito, INA and SK3 of cardiomyocytes, gain- and loss-of-function of cell models were established in mice cardiac fibroblasts and HL-1 atrial myocytes. Dual-luciferase reporter assays and RIP were performed to verify the binding effects between mmu_circ_0005019 and its target microRNA (miRNA). Results In cardiac fibroblasts, mmu_circ_0005019 showed inhibitory effects on cell proliferation and migration. In cardiomyocytes, overexpression of mmu_circ_0005019 promoted Kcnd1, Scn5a and Kcnn3 expression. Knockdown of mmu_circ_0005019 inhibited the expression of Kcnd1, Kcnd3, Scn5a and Kcnn3. Mechanistically, mmu_circ_0005019 exerted biological functions by acting as a miR-499-5p sponge to regulate the expression of its target gene Kcnn3. Conclusions Our findings highlight mmu_circ_0005019 played a protective role in AF development and might serve as an attractive candidate target for AF treatment.

scholarly journals Production, characterization, and cross-reactivity of a polyclonal antibody against Arabidopsis TARGET OF RAPAMYCIN

2019 ◽  
Vol 62 (1) ◽  
Author(s):  
Gyeong-Im Shin ◽  
Sun Young Moon ◽  
Song Yi Jeong ◽  
Myung Geun Ji ◽  
Joon-Yung Cha ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cross Reactivity ◽  
Target Of Rapamycin ◽  
Loss Of Function ◽  
Anticancer Activities ◽  
Purification Method ◽  
E Coli ◽  
Related Family ◽  
Large Gene ◽  
Truncated Variants

AbstractTARGET OF RAPAMYCIN (TOR), a member of the phosphatidylinositol 3-kinase-related family of protein kinases, is encoded by a single, large gene and is evolutionarily conserved in all eukaryotes. TOR plays a role as a master regulator that integrates nutrient, energy, and stress signaling to orchestrate development. TOR was first identified in yeast mutant screens, as its mutants conferred resistance to rapamycin, an antibiotic with immunosuppressive and anticancer activities. In Arabidopsis thaliana, the loss-of-function tor mutant displays embryo lethality, but the precise mechanisms of TOR function are still unknown. Moreover, a lack of reliable molecular and biochemical assay tools limits our ability to explore TOR functions in plants. Here, we produced a polyclonal α-TOR antibody using two truncated variants of TOR (1–200 and 1113–1304 amino acids) as antigens because recombinant full-length TOR is challenging to express in Escherichia coli. Recombinant His-TOR1−200 and His-TOR1113−1304 proteins were individually expressed in E. coli, and a mixture of proteins (at a 1:1 ratio) was used for immunizing rabbits. Antiserum was purified by an antigen-specific purification method, and the purified polyclonal α-TOR antibody successfully detected endogenous TOR proteins in wild-type Arabidopsis and TOR orthologous in major crop plants, including tomato, maize, and alfalfa. Moreover, our α-TOR antibody is useful for coimmunoprecipitation assays. In summary, we generated a polyclonal α-TOR antibody that detects endogenous TOR in various plant species. Our antibody could be used in future studies to determine the precise molecular mechanisms of TOR, which has largely unknown multifunctional roles in plants.

scholarly journals Local anesthetics impair the growth and self-renewal of glioblastoma stem cells by inhibiting ZDHHC15-mediated GP130 palmitoylation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiaoqing Fan ◽  
Haoran Yang ◽  
Chenggang Zhao ◽  
Lizhu Hu ◽  
Delong Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Western Blot ◽  
Local Anesthetics ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Xenograft Model ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Self Renewal

Abstract Background A large number of preclinical studies have shown that local anesthetics have a direct inhibitory effect on tumor biological activities, including cell survival, proliferation, migration, and invasion. There are few studies on the role of local anesthetics in cancer stem cells. This study aimed to determine the possible role of local anesthetics in glioblastoma stem cell (GSC) self-renewal and the underlying molecular mechanisms. Methods The effects of local anesthetics in GSCs were investigated through in vitro and in vivo assays (i.e., Cell Counting Kit 8, spheroidal formation assay, double immunofluorescence, western blot, and xenograft model). The acyl-biotin exchange method (ABE) assay was identified proteins that are S-acylated by zinc finger Asp-His-His-Cys-type palmitoyltransferase 15 (ZDHHC15). Western blot, co-immunoprecipitation, and liquid chromatograph mass spectrometer-mass spectrometry assays were used to explore the mechanisms of ZDHHC15 in effects of local anesthetics in GSCs. Results In this study, we identified a novel mechanism through which local anesthetics can damage the malignant phenotype of glioma. We found that local anesthetics prilocaine, lidocaine, procaine, and ropivacaine can impair the survival and self-renewal of GSCs, especially the classic glioblastoma subtype. These findings suggest that local anesthetics may weaken ZDHHC15 transcripts and decrease GP130 palmitoylation levels and membrane localization, thus inhibiting the activation of IL-6/STAT3 signaling. Conclusions In conclusion, our work emphasizes that ZDHHC15 is a candidate therapeutic target, and local anesthetics are potential therapeutic options for glioblastoma.

Sign in / Sign up

Export Citation Format

Share Document