Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Wilms' tumor-suppressor gene product WT1 coimmunoprecipitates with p53 from baby rat kidney (BRK) cells and Wilms' tumor specimens, and expression of WT1 in BRK cells is associated with increased levels of endogenous wild-type p53 protein. To study the effect of WT1 on p53 function, we cotransfected expression constructs into Saos-2 cells, an osteosarcoma cell line without endogenous expression of either gene. Expression of WT1 resulted in increased steady-state levels of p53, attributable to a prolongation in protein half-life, and associated with protection against papillomavirus E6-mediated degradation of p53. This effect mapped to zinc fingers 1 and 2 of WT1 and was not observed with the closely related EGR1 protein. The stabilized p53 demonstrated enhanced binding to its target DNA sequence and increased trans-activation of a promoter containing this RGC site, but reduced transcriptional repression of a TATA-containing promoter lacking this site. Expression of WT1 inhibited p53-mediated apoptosis triggered by UV irradiation or by expression of temperature-sensitive p53 in the wild-type conformation, but did not affect p53-mediated cell cycle arrest. We conclude that WT1 protein can stabilize p53, modulate its trans-activational properties, and inhibit its ability to induce apoptosis. This effect may contribute to the elevated levels of wild-type p53 protein that are observed in Wilms' tumors.
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PMID:The WT1 gene product stabilizes p53 and inhibits p53-mediated apoptosis. 765 66

Stressful events evoke long-term changes in behavioral responses; however, the underlying mechanisms in the brain are not well understood. Previous work has shown that epigenetic changes and immediate-early gene (IEG) induction in stress-activated dentate gyrus (DG) granule neurons play a crucial role in these behavioral responses. Here, we show that an acute stressful challenge [i.e., forced swimming (FS)] results in DNA demethylation at specific CpG (5'-cytosine-phosphate-guanine-3') sites close to the c-Fos (FBJ murine osteosarcoma viral oncogene homolog) transcriptional start site and within the gene promoter region of Egr-1 (early growth response protein 1) specifically in the DG. Administration of the (endogenous) methyl donor S-adenosyl methionine (SAM) did not affect CpG methylation and IEG gene expression at baseline. However, administration of SAM before the FS challenge resulted in an enhanced CpG methylation at the IEG loci and suppression of IEG induction specifically in the DG and an impaired behavioral immobility response 24 h later. The stressor also specifically increased the expression of the de novo DNA methyltransferase Dnmt3a [DNA (cytosine-5-)-methyltransferase 3 alpha] in this hippocampus region. Moreover, stress resulted in an increased association of Dnmt3a enzyme with the affected CpG loci within the IEG genes. No effects of SAM were observed on stress-evoked histone modifications, including H3S10p-K14ac (histone H3, phosphorylated serine 10 and acetylated lysine-14), H3K4me3 (histone H3, trimethylated lysine-4), H3K9me3 (histone H3, trimethylated lysine-9), and H3K27me3 (histone H3, trimethylated lysine-27). We conclude that the DNA methylation status of IEGs plays a crucial role in FS-induced IEG induction in DG granule neurons and associated behavioral responses. In addition, the concentration of available methyl donor, possibly in conjunction with Dnmt3a, is critical for the responsiveness of dentate neurons to environmental stimuli in terms of gene expression and behavior.
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PMID:Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus. 2707

BACKGROUND Glutamate metabotropic receptor 4 (GRM4) has been correlated with the pathogenesis of osteosarcoma. The objective of this study was to explore the underlying molecular mechanism of GRM4 in osteosarcoma. MATERIAL AND METHODS The expression levels of GRM4 in four human osteosarcoma cell lines and hFOB1.19 cells were examined by real-time quantitative PCR (RT-qPCR). The U2OS cells of the highest GRM4 expression were transfected with lentivirus-mediated small interfering RNA (siRNA). The differentially expressed genes (DEGs) after GRM4 gene silencing were screened through RNA sequencing, and analyzed by bioinformatics. Additionally, the transcription factors (TFs) targeting GRM4 were predicted and the downstream protein-protein interaction (PPI) network was constructed using the bioinformatics approach. RESULTS A total of 51 significant DEGs were obtained, including 14 upregulated and 37 downregulated DEGs. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the DEGs indicated that four significant enrichment pathways were obtained. A total of six TFs that could be involved in the transcriptional regulation of GRM4 were detected. The results showed that 182 genes in the PPI network were significantly enriched in 14 pathways. The chemokines and chemokine receptors were found to be significantly enriched in three pathways. CONCLUSIONS The DEGs in the four significant enrichment pathways might participate in the development and progression of osteosarcoma through GRM4. The results revealed that EGR1 and CTCF are probably involved in the transcriptional regulation of GRM4, which participates in the progress of osteosarcoma by interacting with chemokines and their receptors.
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PMID:To Explore the Mechanism of the GRM4 Gene in Osteosarcoma by RNA Sequencing and Bioinformatics Approach. 2933 16

The present study was to investigate and identify the differentially expressed genes (DEGs) in the transcriptional regulatory network of osteosarcoma (OS). The gene expression dataset from Gene Expression Omnibus (GEO) datasets was downloaded. DEGs were identified and their functional annotation was also conducted. In addition, differentially expressed transcription factors (TFs) and the regulatory genes were identified. The electronic validation was used to verify the expression of selected genes. The integrated analysis led to 932 DEGs. The results of functional annotation indicated that these DEGs significantly enriched in the p53 signaling pathway, Jak-STAT signaling pathway and Wnt signaling pathway. ZNF354C, NFIC, NFATC2, SP2, FOXO3, EGR1, ZEB1, RREB1, EGR2 and SRF were covered by most TFs. The expression levels of NFIC and EGR2 in electronic validation were compatible with our bio-informatics result. In conclusion, the deregulation of these genes may provide valuable information in understanding the underlying molecular mechanism in the OS.
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PMID:Identification of Differentially Expressed Genes under the Regulation of Transcription Factors in Osteosarcoma. 3041 Dec 96

Osteosarcoma (OS) is one of the most common primary bone tumors in children and young adults. The majority of osteosarcoma patients have limited alternative therapeutic options and metastatic patients generally have a poor prognosis. Thus, it is important to explore novel effective therapeutic targets in the treatment of osteosarcoma. Diacylglycerol kinase zeta (DGKZ) is a recently identified gene potentially associated with certain human carcinogenesis. However, the role of DGKZ in proliferation of osteosarcoma is still unclear. In this study, DGKZ's expression was firstly investigated in OS tumor samples and correlated with poor outcome in OS patients. Silence of DGKZ by shRNA hampered osteosarcoma cell growth and promoted cell apoptosis in vitro. In vivo, DGKZ's knockout also suppressed xenograft tumor proliferation as determined by bioluminescence imaging and weight/volume measurements. Meanwhile, Affymetrix GeneChip and Ingenuity Pathway Analysis (IPA) revealed that DGKZ knockdown resulted in a decreased activity of MYC pathway, and several target genes expression in MYC pathway were altered, including CCND1, CDKN2B, CDK6, PCNA, and EGR1. Furthermore, immunoprecipitation coupled with mass spectrometry (IP-MS) analysis was used to identify proteins that interacted with DGKZ in OS cells and revealed ERK1/2, a key MYC-interactor, to associate with DGKZ. Together, our study demonstrated that DGKZ might act as an oncogene in osteosarcoma via its possible interaction with ERK1/2 and MYC pathway.
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PMID:DGKZ Acts as a Potential Oncogene in Osteosarcoma Proliferation Through Its Possible Interaction With ERK1/2 and MYC Pathway. 3066 72

Osteosarcoma is a common malignant bone tumor in children and adolescents under the age of 20. However, research on the pathogenesis and treatment of osteosarcoma is still insufficient. In the present study, based on gene-phenotype correlation network, an analysis was performed to screen disorders related to osteosarcoma. First, we analyzed the differential expression of osteosarcoma in two groups according to different types of osteosarcoma and screened the differentially expressed genes (DEGs) related to osteosarcoma. Further, these DEG coexpression modules were obtained. Finally, we identified a series of regulatory factors, such as endogenous genes, transcription factors (TFs), and ncRNAs, which have potential regulatory effects on osteosarcoma, based on the prediction analysis of related network of gene phenotypes. A total of 3767 DEGs of osteosarcoma were identified and clustered them into 20 osteosarcoma-related dysfunction modules. And there were 38 endogenous genes (including ARF1, HSP90AB1, and TUBA1B), 53 TFs (including E2F1, NFKB1, and EGR1), and 858 ncRNAs (including MALAT1, miR-590-3p, and TUG1) were considered as key regulators of osteosarcoma through a series of function enrichment analysis and network analysis. Based on the results of the present study, we can show a new way for biologists and pharmacists to reveal the potential molecular mechanism of osteosarcoma typing, and provide valuable reference for different follow-up treatment options.
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PMID:Screening of disorders associated with osteosarcoma by integrated network analysis. 3093 65

Osteosarcoma is one of the most aggressive malignant bone tumors worldwide. Although great advancements have been made in its treatment owing to the advent of neoadjuvant chemotherapy, the problem of lung metastasis is a major obstacle in the improvement of survival outcomes. Thus, the aim of the present study is to screen novel and key biomarkers, which may act as potential prognostic markers and therapeutic targets in osteosarcoma. We utilized the robust rank aggregation (RRA) method to integrate three osteosarcoma microarray datasets downloaded from the Gene Expression Omnibus (GEO) database, and we identified the robust differentially expressed genes (DEGs) between primary and metastatic osteosarcoma tissues. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the functions of robust DEGs. The results of enrichment analysis showed that the robust DEGs were closely associated with osteosarcoma development and progression. Immune cell infiltration analysis was also conducted by CIBERSORT algorithm, and we found that macrophages are the most principal infiltrating immune cells in osteosarcoma, especially macrophages M0 and M2. Then, the protein-protein interaction network and key modules were constructed by Cytoscape, and 10 hub genes were selected by plugin cytoHubba from the whole network. The survival analysis of hub genes was also carried out based on the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. The integrated bioinformatics analysis was utilized to provide new insight into osteosarcoma development and metastasis and identified EGR1, CXCL10, MYC, and CXCR4 as potential biomarkers for prognosis of osteosarcoma.
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PMID:Identification of Potential Therapeutic Targets and Immune Cell Infiltration Characteristics in Osteosarcoma Using Bioinformatics Strategy. 3297 2