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Abstract
Prostate transmembrane protein androgen-induced 1 (PMEPA1)/transmembrane prostate androgen-induced protein (TMEPAI), a direct target and a negative regulator of transforming growth factor beta signalling, has an oncogenic role in many cancers. We observed that knockout (KO) of PMEPA1 in human breast cancer cell line MDA-MB-231 using a CRISPR-Cas9 system resulted in reduction of in vivo tumour growth and lung metastasis but not of in vitro monolayer growth capacity of these KO cell lines. This phenomenon was associated with PMEPA1 KO-mediated downregulation of the key proangiogenic factors vascular endothelial growth factor alpha (VEGFA) and interleukin-8 (IL8) that are essential for in vivo but not in vitro growing cells and are also substantial for initiation of lung metastasis.
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Abstract
Neuronal migration is a crucial event in neuronal development for the construction of brain architecture and neuronal networks. Newborn neurons proliferate in the germinal zone and start migration toward their final destination. Migrating neurons adopt different routes, cell shapes and migratory modes depending on extracellular factors and outer physical substrates. Intracellular Ca2+ is an essential second messenger that regulates diverse cellular functions by activating Ca2+-dependent signalling molecules that underlie Ca2+-responsive cellular functions. Neuronal migration during brain architecture construction is no exception. Spontaneous Ca2+ transients are observed in several types of migrating neurons, and a series of Ca2+-dependent signalling molecules governing neuronal migration has been identified. In this review, we first summarize the molecular mechanisms that trigger intracellular Ca2+ elevation in migrating neurons. In the latter half of this review, we provide an overview of the literature on Ca2+-dependent signalling molecules underlying neuronal migration.
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Abstract
VAP (VAMP-associated protein) is a type II integral membrane protein of the endoplasmic reticulum (ER), and its N-terminal major sperm protein (MSP) domain faces the cytoplasmic side. VAP functions as a tethering molecule at the membrane contact sites between the ER and intracellular organelles and regulates a wide variety of cellular functions, including lipid transport, membrane trafficking, microtubule reorganization and unfolded protein response. VAP-point mutations in human vapb are strongly associated with amyotrophic lateral sclerosis. Importantly, the MSP domain of VAP is cleaved, secreted and interacts with the axon growth cone guidance receptors (Eph, Robo, Lar), suggesting that VAP could function as a circulating hormone similar to the Caenorhabditis elegans MSP protein. In this review, we discuss not only the intracellular functions of VAP but also the recently discovered extracellular functions and their implications for neurodegenerative disease.
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Abstract
This study investigated the underlying mechanism of long noncoding RNA (lncRNA) small nucleolar RNA host gene 20 (SNHG20) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). LncRNA SNHG20 and PTEN expression levels were detected by quantitative real-time polymerase chain reaction and western blot. The proliferation of HCC cells was measured by MTT assay, and the apoptosis of HCC cells was measured by flow cytometry analysis. SNHG20 expression level and HBx protein level were upregulated in HBV(+) group than that of HBV(−) group, whereas PTEN protein level was downregulated in HBV(+) group. Besides, SNHG20 was highly expressed in HBV(+) HCC cells than in HBV(−) HCC cells. SNHG20 expression level was positively associated with HBV x protein (HBx) in HCC cells, and HBx–SNHG20 involved in regulating the proliferation and apoptosis of HCC cells. Moreover, SNHG20 was confirmed to interact with PTEN, which negatively regulated PTEN protein level. Finally, we proved HBx–SNHG20–PTEN signalling pathway involved in the regulation of HCC cell proliferation and apoptosis. In vivo experiments showed SNHG20 knockdown inhibited tumour growth of HBV(+) HCC. HBx promoted the proliferation of HCC cell and reduced the apoptosis of HCC cells through the SNHG20/PTEN signalling pathway.
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Abstract
Aberrant glycosylation on tumour cells has been implicated in tumour immune modulation. A recent article published in The Journal of Biochemistry (Sutoh Yoneyama et al., A mechanism for evasion of CTL immunity by altered O-glycosylation of HLA class I, J. Biochem. 2017;161:479–492) showed that bladder cancer cells evaded cytotoxic T lymphocyte-mediated antitumour immunity by a novel mechanism involving the loss of Core 2 structures on human leukocyte antigen Class I O-glycans and subsequent impairment of galectin–glycan lattice formation. The immunosuppressive action of O-glycans on natural killer cell-mediated tumour immunity is also considered an immune evasion system. Furthermore, sialylated O-glycans have been proposed to play a central role in tumour immune escape by modulating the production of immunoregulatory cytokines and growth factors through interactions with sialic acid-binding immunoglobulin-like lectins. Therefore, a better understanding of how alterations in O-glycosylation influence tumour immune evasion will enable the development of novel and more effective therapeutic options for cancer treatment.
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Abstract
Podocytes are terminally differentiated cells that function as the glomerular filtration barrier in the kidney, and podocyte injury leads to serious proteinuria and podocyte leakage into urine. Recent studies have demonstrated that the number of urinary podocytes is correlated with the progression of glomerular diseases. Therefore, urinary podocytes may serve as an indicator of podocyte injury. In this study, to explore podocyte injury-related genes, we performed comprehensive transcriptome analysis of primary rat podocytes cultured in the presence or absence of puromycin aminonucleoside (PAN), an agent commonly used to induce podocyte injury. RNA-seq revealed that a transcript containing the intronic sequence of small nucleolar RNA host gene 4 (Snhg4) was expressed in podocytes and upregulated by PAN. RT-qPCR analysis demonstrated that this transcript, but not Snhg4, was selectively expressed in podocytes. Therefore, we designated the novel transcript Snhg4-pod. 5′- and 3′-RACE experiments revealed that Snhg4-pod is a novel splice variant of Snhg4 lacking a poly(A) tail. PAN induced Snhg4-pod expression in podocytes in a dose-dependent manner along with their mitochondria-mediated apoptotic cell death. Further, Snhg4-pod was detected in urinary sediments from PAN-induced nephrotic rats. Our findings suggest that Snhg4-pod may serve as a novel marker for the diagnosis of glomerular injury.
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Abstract
Heterochromatin protein 1 (HP1) is an evolutionarily conserved chromosomal protein that plays a crucial role in heterochromatin-mediated gene silencing. We previously showed that mammalian HP1α is constitutively phosphorylated at its N-terminal serine residues by casein kinase II (CK2), and that this phosphorylation enhances HP1α’s binding specificity for nucleosomes containing lysine 9-methylated histone H3 (H3K9me). Although the presence of additional HP1α phosphorylation during mitosis was reported more than a decade ago, its biological significance remains largely elusive. Here we found that mitosis-specific HP1α phosphorylation affected HP1α’s ability to bind chromatin. Using biochemical and mutational analyses, we showed that HP1α’s mitotic phosphorylation was located in its hinge region and was reversibly regulated by Aurora B kinase and serine/threonine phosphatases. In addition, chromatin fractionation and electrophoretic mobility shift assays revealed that hinge region-phosphorylated HP1α was preferentially dissociated from mitotic chromatin and exhibited a reduced DNA-binding activity. Although HP1’s mitotic behaviour was previously linked to H3 serine 10 phosphorylation, which blocks the binding of HP1’s chromodomain to H3K9me3, our findings suggest that mitotic phosphorylation in HP1α’s hinge region also contributes to changes in HP1α’s association with mitotic chromatin.
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Abstract
Here, we report the amino acid sequence of Ageritin, the first ribotoxin-like protein from basidiomycetes (Agrocybe aegerita). This protein consists of 135 amino acid residues with a theoretical molecular mass of 14,801.80 Da (experimental mass 14,802.84 Da, [M + H+]+). Unlike both the classic ribotoxins and homologous RNases T1 family from ascomycetes, Ageritin has a single free cysteinyl residue and does not show homology with known RNases endowed with the specific enzymatic activity on the universally conserved Sarcin Ricin Loop. On the other hand, our 3D homology study shows that Ageritin has a structural core consisting of an antiparallel β-sheet and an adjacent long α-helix, typical of ribotoxins and RNase T1 family, although the sheet has an orthogonal arrangement with respect to them. Thus, Ageritin is the first prototype of novel ribotoxin-like protein family from fungi.
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Abstract
Mucin-type O-glycosylation is found not only in mucus proteins, but also in a number of cell membrane and secretory proteins. Several recent studies demonstrate that site-specific O-GalNAc glycosylation plays an important role in regulating protein functions by modulating proteolytic processing. Proteolysis of the amyloid precursor protein (APP) is physiologically important, since cleavages at β and γ positions generate amyloid β (Aβ), a major component in the brain of patients with Alzheimer’s disease. Akasaka-Manya et al. (Excess APP O-glycosylation by GalNAc-T6 decreases Aβ production. J Biochem 2017;161:99–111) showed a specific glycosylation at a site proximal to the β-secretase cleavage site and decreased productions of Aβ1-40 and Aβ1-42 in HEK293T cells transfected with a particular mucin-type glycan initiation enzyme, GalNAc-T6, indicating a novel pharmaceutical strategy to inhibit the production of Aβ through the upregulation of mucin-type O-glycosylation.
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Abstract
Autotaxin (ATX) is a secreted enzyme that produces a bioactive lysophospholipid, lysophosphatidic acid (LPA). ATX plays a role in vascular and neural development in embryos but its mechanisms remain unclear. At the beginning of this study, only one zebrafish atx gene (atxa) was known and had been investigated. In this study, we generated ATX knockout (KO) fish by TALEN targeting atxa. Unexpectedly, atxa KO fish showed neither vascular defects nor reduction of ATX activity, implying the existence of one or more other ATXs in the genome. By a BLAST search using ATXa protein fragments as a query, we found a genomic sequence that closely resembled atxa exons 13, 14 and 15. Consequently, we cloned a cDNA encoding a second zebrafish autotaxin (ATXb), and found that it was transcribed in various tissues. The atxb gene encoded a protein of 832 amino acids (compared to 850 amino acids in ATXa) with 60% amino acid identity to ATXa and clustered with ATXs from other species. A recombinant ATXb protein showed lysophospholipase D (lysoPLD) activities with substrate specificities similar to those of ATXa and mammalian ATXs. These results indicate that ATXb is a second zebrafish ATX, which possibly shares redundant roles with ATXa in embryonic development.
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