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Activation of mammalian Tolloid-like 1 expression by hypoxia in human neuroblastoma SH-SY5Y cells.

ABSTRACT: Mammalian Tolloid-like 1 (mTll-1) is an astacin metalloprotease that is a member of the Tolloid family of proteins. mTll-1 cleaves chordin, an inhibitor of bone morphogenetic proteins (BMPs) and potentiates activity of the BMPs. Prenatal stress and glucocorticoids decrease mTll-1 expression whereas voluntary exercise increase mTll-1 gene expression in the mouse hippocampus. Here, we studied the underlying molecular mechanisms by which hypoxia regulates human mTll-1 gene expression. When cells were subjected to hypoxia, the expression of endogenous mTll-1 was upregulated in SH-SY5Y human neuroblastoma cells. Dual-luciferase assay and site-directed mutagenesis showed the presence of hypoxia responsive elements (HREs) at position 625 that was essential for activation of mTll-1 expression under hypoxic conditions. The binding of hypoxia-inducible factor (HIF-1) protein to the HREs was confirmed by gel shift assay. These results indicate that the HRE motif is directly involved in the activation of the mTll-1 transcription under hypoxic conditions.

SUBMITTER: Sabirzhanova IB

PROVIDER: S-EPMC2754799 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Activation of mammalian Tolloid-like 1 expression by hypoxia in human neuroblastoma SH-SY5Y cells.

Sabirzhanova Inna B IB Sabirzhanov Boris E BE Keifer Joyce J Clark Timothy G TG

Biochemical and biophysical research communications 20090831 2

Mammalian Tolloid-like 1 (mTll-1) is an astacin metalloprotease that is a member of the Tolloid family of proteins. mTll-1 cleaves chordin, an inhibitor of bone morphogenetic proteins (BMPs) and potentiates activity of the BMPs. Prenatal stress and glucocorticoids decrease mTll-1 expression whereas voluntary exercise increase mTll-1 gene expression in the mouse hippocampus. Here, we studied the underlying molecular mechanisms by which hypoxia regulates human mTll-1 gene expression. When cells we ...[more]

PMID: 19723501

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Project description:BackgroundMaleic acid is a multi-functional chemical widely used in the field of industrial chemistry for producing food additives and food contact materials. As maleic acid may contaminate food by the release from food packages or intentional addition, it raises the concern about the effects of excessive dietary exposure to maleic acid on human health. However, the influence of maleic acid on human health has not been thoroughly studied. In silico toxicogenomics approaches have found the association between maleic acid and nervous system disease in human. The aim of this study is to experimentally explore the effects of maleic acid on human neuronal cells.MethodsA microarray-based transcriptome profiling was performed to offer a better understanding of the effects of maleic acid on human health. Gene expression profiles of human neuroblastoma SH-SY5Y cells exposed to three concentrations of maleic acid (10, 50, and 100 μM) for 24 h were analyzed. Genes which were differentially expressed in dose-dependent manners were identified and further analyzed with an enrichment analysis. The expression profile of selected genes related to the inferred functional changes was validated using quantitative polymerase chain reaction (qPCR). Specific fluorescence probes were applied to observe the inferred functional changes in maleic acid-treated neuronal cells.ResultsA total of 316 differentially expressed genes (141 upregulated and 175 downregulated) were identified in response to the treatment of maleic acid. The enrichment analysis showed that DNA binding and metal ion binding were the significant molecular functions (MFs) of the neuronal cells affected by maleic acid. Maleic acid exposure decreased the expression of genes associated with calcium and thiol levels of the cells in a dose-dependent manner. The levels of intracellular calcium and thiol levels were also affected by maleic acid dose-dependent.DiscussionThe exposure to maleic acid is found to decrease the cellular calcium and thiol levels in human neuronal cells at both transcriptional and functional levels. This study reported the first transcriptomic profiling of human neuronal cells treated with maleic acid. It is also the first experimental validation of chemical effects predicted by in silico toxicogenomics approaches. The proposed approach may be useful in understanding the potential effects of other poorly characterized chemicals on human health.

Project description:Toxoplasma rhoptry protein 16 (ROP16) is crucial in the host-pathogen interaction by acting as a virulent factor during invasion. To improve understanding of the molecular function underlying the effect of ROP16 on host cells, the present study analyzed the transcriptional profile of genes in the ROP16?transfected SH?SY5Y human neuroblastoma cell line. The transcriptional profile of the SH?SY5Y human neuroblastoma cell line overexpressing ROP16 were determined by microarray analysis in order to determine the host neural cell response to the virulent factor. Functional analysis was performed using the Protein Analysis Through Evolutionary Relationships classification system. The ToppGene Suite was used to select candidate genes from the differentially expressed genes. A protein?protein interaction network was constructed using Cytoscape software according to the interaction associations determined using the Search Tool for the Retrieval of Interacting Genes/Proteins. Reverse transcription?quantitative polymerase chain reaction (RT?qPCR) analysis of the selected genes confirmed the results of the microarray. The results showed that 383 genes were differentially expressed in response to ROP16 transfection, of which 138 genes were upregulated and 245 genes were downregulated. Functional analysis indicated that the differentially expressed genes (DEGs) were involved in several biological processes, including developmental process, biological regulation and apoptotic process. A total of 15 candidate genes from the DEGs were screened using the ToppGene Suite. No significant differences in expression were observed between the RT?qPCR data and the microarray data. Transfection with ROP16 resulted in alterations of several biological processes, including nervous system development, apoptosis and transcriptional regulation. Several genes, including CXCL12, BAI1, ZIC2, RBMX, RASSF6, MAGE?A6 and HOX, were identified as significant DEGs. Taken together, these results may contribute to understanding the mechanisms underlying the functions of ROP16 and provide scope for further investigation of the pathogenesis of Toxoplasma gondii.

Dataset Information

Activation of mammalian Tolloid-like 1 expression by hypoxia in human neuroblastoma SH-SY5Y cells.

Publications

Activation of mammalian Tolloid-like 1 expression by hypoxia in human neuroblastoma SH-SY5Y cells.

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