1,720,970 research outputs found
The role of transmembrane immunoglobulin domain containing-1 (TMIGD1) in renal epithelial cells
Full text linkKidney disease has a high incidence across the globe and can be caused by acute and chronic injury. Current methods of treatment range from prevention and management with diet and extend to hemodialysis at End Stage Renal Disease (ESRD). Transmembrane Immunoglobulin Domain Containing-1 (TMIGD1) is mainly expressed in kidney and the intestines and is involved in cell-cell interaction of epithelial cells. This thesis investigated the potential role of TMIGD1 in the development of chronic kidney disease and tubular epithelial cell injury in CRISPR/Cas9-TMIGD1 transgenic mouse. Treatment of wild-type mice with adenine showed that TMIGD1 is downregulated in response to adenine-induced renal cell injury. CRISPR/Cas9-TMIGD1 -/+ mice treated with adenine displayed significantly increased tubular damage compared to wild-type mice. Additionally, expression of TMIGD1 was directly correlated with localization of C/EBPβ to nucleus, a transcription factor that is known to regulate expression of TMIGD1. In conclusion, the loss of TMIGD1 negatively impacts response to renal stress.2020-06-17T00:00:00
Characterization of IGCR-1: a novel molecule with potential roles in lung carcinogenesis
Full text linkNon-small cell lung cancer (NSCLC) patients respond poorly to generic chemotherapeutics. Despite recent advancements in the treatment of NSCLC, the overall five-year survival rate of NSCLC remains low at 14.6%. We have identified Immunoglobulin-containing and Cysteine-rich Receptor (IGCR-1) as a putative cell surface protein, which is expressed in lung epithelial cells.
The main objectives of this study were to evaluate expression of IGCR-1 in normal lung epithelium and lung carcinoma. Our analysis of publicly available ATCG data via bioGPS revealed that IGCR-1 is highly expressed in human lung. Moreover, our immunohistochemical studies further confirmed that IGCR-1 is expressed in bronchial epithelial cells. Additionally, IGCR-1 is expressed in endothelial cells of blood vessels and localized on the cell surface of human embryonic kidney cells. Its cell surface localization suggests that IGCR-1 could be a cellular adhesion molecule (CAM) with roles in the tumor microenvironment. Of note, the analysis of a panel of human lung carcinoma cell lines via western blot analysis demonstrated that IGCR-1 is expressed at variable levels in these cell lines. Given the heterogeneity of NSCLSs and the corresponding differential expression of IGCR-1 in different lung cancer cell lines, IGCR-1 may play an important role in NSCLCs.2020-06-17T00:00:00
Identification of the lysine methyltransferase involved in the methylation of VEGFR-2
Full text linkAngiogenesis is the process of new blood vessel growth from preexisting vessels. This process relies on the activity of Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) and occurs in both normal and pathological tissues. Angiogenesis is often dysregulated in diseases such as cancer and many efforts have been made to treat such diseases by targeting the VEGFR-2 pathway. VEGFR-2 is activated upon ligand binding and subsequent autophosphorylation of tyrosine residues in the kinase domain, which leads to endothelial cell survival, proliferation, and growth – all of which are required for angiogenesis to occur.
It was previously demonstrated that methylation of VEGFR-2 at Lys1041 enhanced its tyrosine autophosphorylation and is required for VEGFR-2 mediated angiogenesis in zebrafish and tumor growth in mouse. However, the Lysine Methyltransferase (KMT) involved in the methylation of VEGFR-2 remains unknown. This study aimed to identify the KMT involved in the methylation of VEGFR-2.
We have identified Enhancer of zeste homolog 2 (EZH2) as the KMT likely responsible for catalyzing methylation of K1041 on VEGFR-2. Over-expression of EZH2 was found to increase phosphorylation of Tyr1054, one of the required phosphorylation sites for VEGFR-2 activation, in whole cell lysates and VEGFR-2 purified by immunoprecipitation. The effect of over-expression of EZH2 in the phosphorylation of VEGFR-2 at Tyr1054 was dose-dependent - increasing concentrations of EZH2 resulted in increasing phosphorylation of VEGFR-2 at Tyr1054. Moreover, we determined that EZH2 physically interacts with VEGFR-2 as demonstrated by co-immunoprecipitation in vitro GST-pulldown assays. The C-terminus of EZH2 (amino acids 371-746), physically interacted with VEGFR-2. Taken together, we have identified EZH2 as a candidate KMT involved in the methylation of Lys1041, which increases phosphorylation of VEGFR-2 at Tyr1054.2020-07-03T00:00:00
Role of ubiquitination in IGPR-1 regulation
Full text linkImmunoglobulin-containing and proline-rich receptor-1 (IGPR-1), is a newly identified cell adhesion molecule and is expressed in various cell types including, epithelial and endothelial cell origin. IGPR-1 regulates cell-cell adhesion and promotes angiogenesis, activated by shear stress and mediates endothelial cells response to shear stress. Moreover, IGPR-1 expression is upregulated in colon cancer and supports colon tumor growth. IGPR-1 contains a single extracellular immunoglobulin domain, a transmembrane domain and followed by a cytoplasmic proline-rich C-terminus.
We demonstrate that ubiquitin E3 protein ligase neural precursor cell expressed developmentally down regulated 4 (NEDD4) binds to and ubiquitinates IGPR-1. Furthermore, among the four WW domains, the C-terminus WW domain#4 selectively mediates the binding of NEDD4 with IGPR-1. We used in vitro ubiquitination assay and identified UbcH6, as an E2 conjugating enzyme required for NEDD4-mediated ubiquitination of IGPR-1. Taken together, our data identifies NEDD4/Ubc6H ubiquitination system as a major pathway involved in the ubiquitination of IGPR-1.2021-06-08T00:00:00
The role of transmembrane immunoglobulin domain containing-1 in colon cancer
Full text linkColorectal Cancer (CRC) is one of the most common cancers worldwide. Although various genetic and environmental mechanisms have been identified, the full molecular mechanisms deriving CRC tumorigenesis remain largely unknown. Transmembrane and Immunoglobulin Domain Containing-1 (TMIGD1) is a newly identified candidate tumor suppressor that is mainly expressed in the kidneys and intestines. However, whether TMIGD1 is involved in the tumorigenesis of CRC is not currently known. The main objective of this project was to investigate the effects of the loss of TMIGD1 on intestinal morphology and cellular differentiation in wildtype and knockout mice. Our findings illustrate that the loss of TMIGD1 causes intestinal adenomas and disrupts intestinal brush border formation in mouse models. Furthermore, our research shows that the loss of TMIGD1 in mice affects cellular maturation and intestinal epithelium differentiation. We also demonstrate that TMIGD1 is downregulated in human CRC tissue. Taken together, our results reveal that the loss of TMIGD1 in mouse colonic epithelium results in impaired intestinal epithelium brush border formation, junctional polarity, and development of colonic adenoma.2021-06-04T00:00:00
HHLA2 & IGPR1 roles in tumor progression and metastasis
Full text linkThe metastatic pathways determine the process by which cancer cells give rise to a metastatic lesion in a new tissue or organ. Cell-cell adhesion is a central aspect of many of these metastatic pathways. Cell adhesion molecules belonging to the immunoglobulin superfamily (Ig-SF) commonly play a central role in cell-cell adhesion, and a number of these molecules have been associated with cancer progression and a metastatic phenotype. HERV-H LTR-associating protein 2 (HHLA2) and immunoglobulin-containing and proline-rich receptor-1 (IGPR1) are two recently discovered IG-SF cellular adhesion molecules of the B7 and CD 28 family that are overexpressed in several cancer cell lines and contribute to increased growth, metastatic phenotype and decreased immune cell infiltration status. Regarding the accumulating evidence on the potential interaction between IGPR1 and HHLA2 in immune regulation we sought to explore the effects of this proposed interaction in the phosphorylation of IGPR1 on SER220. Our results show that HHLA2 reduces phosphorylation of IGPR1 at Ser220 in a in vitro co-culture assay. Taken together, our data suggests that IGPR-1/HHLA2 pathway could regulate cell invasion and metastasis by stimulating and increased prosurvival and metastatic phenotype
The role of BET proteins in castration-resistant prostate cancer dissemination
Full text linkThe inevitable progression of advanced prostate cancer to castration resistance, and ultimately to lethal metastatic disease, depends on primary or acquired resistance to conventional androgen-deprivation therapy (ADT) and accumulated resistance mechanisms to evade androgen receptor (AR) suppression. Whereas the canonical androgen/AR signaling axis maintains prostate cell growth, differentiation and survival, in prostate cancer cells, AR adaptations that arise in response to ADT are not singular, but diverse, and include gene amplification, mutation and even complete loss of receptor expression. Collectively, each of these AR adaptations contributes to a complex, heterogenous, ADT-resistant tumor that culminates in prostate tumor cells transitioning from epithelial to mesenchymal states (EMT) and the development of metastatic castration-resistant prostate cancer (mCRPC). Here, we examined prostate cancer cell lines that model common CRPC subtypes, each with different AR composition, and focused on novel regulators of tumor progression, the Bromodomain and ExtraTerminal (BET – BRD2, BRD3 and BRD4) family of proteins, to test the hypothesis that each BET family member regulates EMT and underlying characteristics such as cell motility and invasiveness. We systematically manipulated the BET proteins and found that BRD4
regulates cell migration and invasion across all models of CRPC, regardless of aggressiveness and AR status, whereas BRD2 and BRD3 only regulate cell migration and invasion in less aggressive models that retain AR expression or signaling. We determined that BRD4’s contribution to this process occurs through the transcriptional regulation of AHNAK, SNAI1 and SNAI2, which are EMT genes linked to promotion of metastasis in a diverse set of cancers. Furthermore, treatment of CRPC cell lines with low doses of MZ1, a small-molecule, BRD4-selective degrader, inhibits EMT and metastatic potential. Overall, these results reveal a novel, BRD4-regulated EMT gene signature that may be targetable to treat metastatic castration-resistant prostate cancer
IGPR-1 interacts with MIA to regulate melanoma cell migration and invasion
Full text linkMelanoma represents one of the most aggressive and deadliest form of skin cancer. Melanoma inhibitory activity (MIA) also called cartilage-derived retinoic acid-sensitive protein (CD-RAP) is a small secreted protein with a single Src Homology 3 (SH3) domain-like fold with N- and C-terminal extensions. MIA interacts with extracellular matrix proteins (ECM), such as fibronectin, laminin, tenascin, ECM receptors and integrins. It is proposed that MIA by interacting with ECM or integrins inhibits cell-ECM adhesion leads to increased melanoma cell migration and tumor invasion. However, the experimental data to support this proposed function of MIA remains poorly understood. We have identified immunoglobulin-containing and proline-rich receptor-1 (IGPR-1) as a novel binding partner for MIA. The main objectives of this project were to investigate IGPR-1 expression in human melanoma cell lines and primary tumors and explore the biological importance of IGPR-1/MIA axis in melanoma cell function. Our findings revealed that IGPR-1 expression is downregulated in melanoma cell lines. However, different levels of IGPR-1 expression have been observed. Moreover, IGPR-1 expression was significantly downregulated in human primary melanoma tumors. We demonstrate that co-expression of IGPR-1with MIA promotes cell survival and increase cell-cell adhesion. Taken together, our data suggests that IGPR-1/MIA pathway could regulate melanoma cell invasion and metastasis. We propose a novel cytosolic signaling function for MIA in melanoma cells.2020-02-20T00:00:00
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
- …
