Molecular structure, gene expression and functional role of WFDC1 in angiogenesis and cancer

2021 ◽  
Author(s):  
Sipin Zhu ◽  
Lin Ye ◽  
Samuel Bennett ◽  
Huazi Xu ◽  
Dengwei He ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Structure ◽  
Functional Role

Biologic consequences of androgen receptor (AR) activity in MDV3100-resistant LNCaP cells and dependence on AR full length.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 74-74
Author(s):  
Yoshiaki Yamamoto ◽  
Yohann Loriot ◽  
Eliana Beraldi ◽  
Tianyuan Zhou ◽  
Youngsoo Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Androgen Receptor ◽  
Cell Growth ◽  
Functional Role ◽  
Full Length ◽  
Lncap Cells ◽  
Exon 1

74 Background: While recent reports link androgen receptor (AR) variants (AR-Vs) to castration resistant prostate cancer (CRPC), the biological significance of AR-Vs in AR-regulated cell survival and proliferation, independent of AR full length (AR-FL), remains controversial. To define the functional role of AR-FL and AR-Vs in MDV3100-resistant (MDV-R), we designed antisense oligonucleotide (ASO) targeting exon 1 and exon 8 in AR to knockdown AR-FL alone or in combination with AR-Vs and examined these effects in MDV-R LNCaP-derived cells in vitro and in vivo. Methods: We generated by selection MDV-R LNCaP-derived sub-lines that uniformly expressed high levels of both AR-FL and AR-V7 compared to CRPC LNCaP xenografts. Cell growth rates, protein and gene expression were analyzed using crystal violet assay, western blotting and real-time PCR, respectively. Exon 1 and 8 AR-ASO were evaluated in MDV-R49F CRPC LNCaP xenografts. Results: AR-V7 was transiently transfected in MDV-R49F cells and differential knockdown of AR-V7 and/or AR-FL by exon 1 versus exon 8 AR-ASO was used to evaluate relative biologic contributions of AR-FL versus AR-V7 in MDV-R LNCaP AR-V7 overexpressing cells. Exon 1 and 8 AR-ASO treatment in these cells similarly decreased prostate-specific antigen (PSA) expression and induced apoptosis as measured by caspase-3 and PARP cleavage and cell growth inhibition. To further define the functional role of AR-Vs in MDV-R LNCaP cells, we used a CE3 siRNA that specifically silenced AR-V7, but not AR-FL in MDV-R LNCaP cells. AR-V7 knockdown did not decrease PSA levels, did not induce apoptosis, and did not inhibit cell growth. In MDV-R LNCaP cells, exon 1 and 8 ASO similarly suppressed cell growth and AR-regulated gene expression in vitro and in vivo. Conclusions: These results indicate that the AR remains an important driver of MDV3100 resistance and, the biologic consequences mainly driven by AR-FL in MDV-R LNCaP models.

scholarly journals Functional roles of COMP and TSP-4 in articular cartilage and their relevance in osteoarthritis

2021 ◽  
Author(s):  
◽  
Kathrin Maly
Keyword(s):  
Gene Expression ◽  
Articular Cartilage ◽  
Protein Level ◽  
Functional Role ◽  
Human Articular Cartilage ◽  
Serum Samples ◽  
Superficial Zone ◽  
Ecm Proteins ◽  
Healthy Cartilage

Osteoarthritis (OA) is a slowly progressing disease, resulting in the degradation of cartilage and the loss of joint functionality. The cartilage extracellular matrix (ECM) is degraded and undergoes remodelling in OA progression. Chondrocytes start to express degrading proteases but are also reactivated and synthesise ECM proteins. The spectrum of these newly synthesised proteins and their involvement in OA specific processes and cartilage repair is hardly investigated. Human articular cartilage obtained from OA patients undergoing knee replacement surgery was evaluated according to the OARSI histopathology grading system. Healthy, non-OA cartilage samples were used as controls. The expression and distribution of thrombospondin-4 (TSP-4) and the closely related COMP were analysed on the gene level by PCR and on the protein level by immunohistology and immunoblot assays. The potential of TSP-4 as a diagnostic marker was evaluated by immunoblot assays, using serum samples from OA patients and healthy individuals. The functional role of both proteins was further investigated in in vitro studies using chondrocytes isolated from femoral condyles of healthy pigs. The effect of COMP and TSP-4 on chondrocyte migration and attachment was investigated via transwell and attachment assays, respectively. Moreover, the potential of COMP and TSP-4 to modulate the chondrocyte phenotype by inducing gene expression, ECM protein synthesis and matrix formation was investigated by immunofluorescence staining and qPCR. The activation of cartilage relevant signalling pathways was investigated by immunoblot assays. These results showed for the first time the presence of TSP-4 in articular cartilage. Its amount dramatically increased in OA compared to healthy cartilage and correlated positively with OA severity. In healthy cartilage TSP-4 was primarily found in the superficial zone while it was wider distributed in the middle and deeper zones of OA cartilage. The amount of specific TSP-4 fragments was increased in sera of OA patients compared to healthy controls, indicating a potential to serve as an OA biomarker. COMP was ubiquitously expressed in healthy cartilage but degraded in early as well as re-expressed in late-stage OA. The overall protein levels between OA severity grades were comparable. Contrary to TSP-4, COMP was localised primarily in the upper zone of OA cartilage, in particular in areas with severe damage. COMP could attract chondrocytes and facilitated their attachment, while TSP-4 did not affect these processes. COMP and TSP 4 were generally weak inducers of gene expression, although both could induce COL2A1 and TSP-4 additionally COL12A1 and ACAN after 6 h. Correlating data were obtained on the protein level: COMP and TSP-4 promoted the synthesis and matrix formation of collagen II, collagen IX, collagen XII and proteoglycans. In parallel, both proteins suppressed chondrocyte hypertrophy and dedifferentiation by reducing collagen X and collagen I. By analysing the effect of COMP and TSP-4 on intracellular signalling, both proteins induced Erk1/2 phosphorylation and TSP-4 could further promote Smad2/3 signalling induced by TGF-β1. None of the two proteins had a direct or modulatory effect on Smad1/5/9 dependent signalling. In summary, COMP and TSP-4 contribute to ECM maintenance and repair by inducing the expression of essential ECM proteins and suppressing chondrocyte dedifferentiation. These effects might be mediated by Erk1/2 phosphorylation. The presented data demonstrate an important functional role of COMP and TSP-4 in both healthy and OA cartilage and provide a basis for further studies on their potential in clinical applications for OA diagnosis and treatment.

scholarly journals The role of insulators and transcription in 3D chromatin organisation of flies

2021 ◽  
Author(s):  
Keerthi T Chathoth ◽  
Liudmila A Mikheeva ◽  
Gilles Crevel ◽  
Jareth C. Wolfe ◽  
Ioni Hunter ◽  
...  
Keyword(s):  
Gene Expression ◽  
Differential Expression ◽  
Differentially Expressed Genes ◽  
Functional Role ◽  
Transcriptomic Data ◽  
Chromatin Loops ◽  
Topologically Associating Domains ◽  
Architectural Proteins ◽  
Chromatin Organisation

AbstractThe DNA in many organisms, including humans, is shown to be organised in topologically associating domains (TADs). InDrosophila, several architectural proteins are enriched at TAD borders, but it is still unclear whether these proteins play a functional role in the formation and maintenance of TADs. Here, we show that depletion of BEAF-32, Cp190, Chro and Dref leads to changes in TAD organisation and chromatin loops. Their depletion predominantly affects TAD borders located in heterochromatin, while TAD borders located in euchromatin are resilient to these mutants. Furthermore, transcriptomic data has revealed hundreds of genes displaying differential expression in these mutants and showed that the majority of differentially expressed genes are located within reorganised TADs. Our work identifies a novel and functional role for architectural proteins at TAD borders inDrosophilaand a link between TAD reorganisation and subsequent changes in gene expression.

scholarly journals A multiscale model of complex endothelial cell dynamics in early angiogenesis

2020 ◽  
Author(s):  
Daria Stepanova ◽  
Helen M. Byrne ◽  
Philip K. Maini ◽  
Tomás Alarcón
Keyword(s):  
Gene Expression ◽  
Experimental Data ◽  
Endothelial Cells ◽  
Functional Role ◽  
Experimental Studies ◽  
Multiscale Model ◽  
Vascular Network ◽  
Vascular Networks ◽  
Vascular Bed

AbstractWe introduce a hybrid two-dimensional multiscale model of angiogenesis, the process by which endothelial cells (ECs) migrate from a pre-existing vascular bed in response to local environmental cues and cell-cell interactions, to create a new vascular network. Recent experimental studies have highlighted a central role of cell rearrangements in the formation of angiogenic networks. Our model accounts for this phenomenon via the heterogeneous response of ECs to their microenvironment. These cell rearrangements, in turn, dynamically remodel the local environment. The model reproduces characteristic features of angiogenic sprouting that include branching, chemotactic sensitivity, the brush border effect, and cell mixing. These properties, rather than being hardwired into the model, emerge naturally from the gene expression patterns of individual cells. After calibrating and validating our model against experimental data, we use it to predict how the structure of the vascular network changes as the baseline gene expression levels of the VEGF-Delta-Notch pathway, and the composition of the extracellular environment, vary. In order to investigate the impact of cell rearrangements on the vascular network structure, we introduce the mixing measure, a scalar metric that quantifies cell mixing as the vascular network grows. We calculate the mixing measure for the simulated vascular networks generated by ECs of different lineages (wild type cells and mutant cells with impaired expression of a specific receptor). Our results show that the time evolution of the mixing measure is directly correlated to the generic features of the vascular branching pattern, thus, supporting the hypothesis that cell rearrangements play an essential role in sprouting angiogenesis. Furthermore, we predict that lower cell rearrangement leads to an imbalance between branching and sprout elongation. Since the computation of this statistic requires only individual cell trajectories, it can be computed for networks generated in biological experiments, making it a potential biomarker for pathological angiogenesis.Author summaryAngiogenesis, the process by which new blood vessels are formed by sprouting from the pre-existing vascular bed, plays a key role in both physiological and pathological processes, including tumour growth. The structure of a growing vascular network is determined by the coordinated behaviour of endothelial cells in response to various signalling cues. Recent experimental studies have highlighted the importance of cell rearrangements as a driver for sprout elongation. However, the functional role of this phenomenon remains unclear. We formulate a new multiscale model of angiogenesis which, by accounting explicitly for the complex dynamics of endothelial cells within growing angiogenic sprouts, is able to produce generic features of angiogenic structures (branching, chemotactic sensitivity, cell mixing, etc.) as emergent properties of its dynamics. We validate our model against experimental data and then use it to quantify the phenomenon of cell mixing in vascular networks generated by endothelial cells of different lineages. Our results show that there is a direct correlation between the time evolution of cell mixing in a growing vascular network and its branching structure, thus paving the way for understanding the functional role of cell rearrangements in angiogenesis.

scholarly journals Corticotropin-releasing hormone signals adversity in both the placenta and the brain: regulation by glucocorticoids and allostatic overload

1999 ◽  
Vol 161 (3) ◽  
pp. 349-356 ◽  
Author(s):  
J Schulkin
Keyword(s):  
Gene Expression ◽  
Preterm Labor ◽  
Functional Role ◽  
Stria Terminalis ◽  
Corticotropin Releasing Hormone ◽  
Bed Nucleus ◽  
Releasing Hormone ◽  
The Brain ◽  
Hormone Signals

Glucocorticoids regulate corticotropin-releasing hormone (CRH) gene expression in the placenta and the brain. In both the placenta and two extrahypothalamic sites in the brain (the amygdala and the bed nucleus of the stria terminalis), glucocorticoids elevate CRH gene expression. One functional role of the elevation of CRH by glucocorticoids may be to signal adversity. When CRH is over-expressed in the placenta, it may indicate that the pregnancy is in danger, and preterm labor may result. When CRH is over-expressed in the brains of animals, they may become more fearful. Both situations possibly reflect allostatic mechanisms and vulnerability to allostatic overload, a condition in which biological tissue may be compromised.

scholarly journals Hypothesis of the conjunct expression gene: can random mutation explain the phenotypic variability?

2018 ◽  
Author(s):  
Víctor A Zapata Trejo
Keyword(s):  
Gene Expression ◽  
Natural Selection ◽  
Functional Role ◽  
Germ Line ◽  
Phenotypic Variability ◽  
Point Of View ◽  
Random Mutation ◽  
Undifferentiated Cells ◽  
Gene Expression Levels

If the environmental conditions can or not influence in the phenotype evolution, is a topic that has been discussed during the last ten years. The epigenome regulates the gene expression of all cells and indicates which specific genes must be transcribed. It is argued that the expression factors that act in specific genes of the somatic cells involved in a behavior also act in the partial transcription of the same genes in the most undifferentiated cells of the germ line. The functional role of the isochores as an epigenetic determinant regulator of the transcription and therefore of gene expression levels is discussed. It is proposed how a probabilistic view of the random mutation can integrate all the evidence pointing to a conjunct phenotype evolution with the environment. This work provides a new point of view on how the environment can influence in adaptation through natural selection considering the theory currently accepted.

scholarly journals MicroRNA Response Elements-Mediated miRNA-miRNA Interactions in Prostate Cancer

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Mohammed Alshalalfa
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Cancer Progression ◽  
Biological Networks ◽  
Functional Role ◽  
Systems Perspective ◽  
Mrna Gene ◽  
Mrna Gene Expression ◽  
Tumor Suppressor Mirnas

The cell is a highly organized system of interacting molecules including proteins, mRNAs, and miRNAs. Analyzing the cell from a systems perspective by integrating different types of data helps revealing the complexity of diseases. Although there is emerging evidence that microRNAs have a functional role in cancer, the role of microRNAs in mediating cancer progression and metastasis remains not fully explored. As the amount of available miRNA and mRNA gene expression data grows, more systematic methods combining gene expression and biological networks become necessary to explore miRNA function. In this work I integrated functional miRNA-target interactions with mRNA and miRNA expression to infer mRNA-mediated miRNA-miRNA interactions. The inferred network represents miRNA modulation through common targets. The network is used to characterize the functional role of microRNA response element (MRE) to mediate interactions between miRNAs targeting the MRE. Results revealed that miRNA-1 is a key player in regulating prostate cancer progression. 11 miRNAs were identified as diagnostic and prognostic biomarkers that act as tumor suppressor miRNAs. This work demonstrates the utility of a network analysis as opposed to differential expression to find important miRNAs that regulate prostate cancer.

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