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 alternative reading frame (ARF) tumor suppressor exerts both p53-dependent and p53-independent functions. The corepressor C-terminal binding protein (CtBP) interacts with ARF, resulting in proteasome-mediated degradation of CtBP. ARF can induce apoptosis in p53-null colon cancer cells, in a manner dependent on ARF interaction with CtBP. Bik was uniquely identified in an apoptotic gene array as coordinately upregulated in colon cancer cells after either CtBP2 knockdown or ARF overexpression. Validating the array findings, ARF induced Bik mRNA and protein expression, and this activity required an intact CtBP binding domain. Apoptosis induced by CtBP deficiency was substantially impaired when Bik expression was simultaneously silenced. An analysis of the Bik promoter revealed binding sites for the CtBP-interacting basic Kruppel-like factor (BKLF). A Bik promoter luciferase reporter was repressed by BKLF and CtBP2, and ARF reversed CtBP-associated repression. Chromatin immunoprecipitation analyses showed that CtBP was recruited to the Bik promoter largely by BKLF. Expression profiling of BH3-only gene expression in ARF-expressing or CtBP-deficient cells revealed that Bik was uniquely regulated by ARF/CtBP in colon cancer cells, whereas additional BH3-only proteins (Bim, Bmf) showed CtBP-dependent repression in osteosarcoma cells. ARF antagonism of CtBP repression of Bik and other BH3-only genes may have a critical role in ARF-induced p53-independent apoptosis and tumor suppression.
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PMID:An ARF/CtBP2 complex regulates BH3-only gene expression and p53-independent apoptosis. 1979 4

Carboxyl-terminal binding protein 1 (CtBP1), a well-known transcriptional co-repressor, is highly expressed in a number of cancer types. However, it is still absent in osteosarcoma cells. Here, we found that CtBP1, but not CtBP2, is overexpressed in invasive osteosarcoma tissues and cells. The overexpressed CtBP1 in turn represses its downstream targets, such as the pro-apoptotic regulators Bax, Bim and p53 upregulated modulator of apoptosis (PUMA), cell adhesion molecule E-cadherin, and the cell cycle regulators p16, p21 and phosphatase and tensin homolog (PTEN). To explore the molecular mechanism of CtBP1 overexpression, we subjected three independent clinical samples to miRNA microarray analysis and found that miR-485-3p could specifically bind to the 3'-untranslated region (3'-UTR) of CtBP1, thereby negatively controlling CtBP1 expression. The overexpression of miR-485-3p in osteosarcoma cells significantly repressed CtBP1 levels and inhibited cell proliferation, colony formation, cell migration and sphere formation. Further analysis indicated that DNA hypermethylation in the promoter region of miR-485-3p caused the downregulation of miR-485-3p. Treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine (AZA) resulted in the upregulation of miR-485-3p and the downregulation of CtBP1 as well as inhibited osteosarcoma cell growth. This study provides evidence that CtBP1 is also overexpressed in osteosarcoma cells and demonstrates the underlying mechanism regarding its overexpression. Thus, therapeutically targeting CtBP1 may represent an effective strategy for osteosarcoma therapy.
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PMID:MicroRNA485-3p negatively regulates the transcriptional co-repressor CtBP1 to control the oncogenic process in osteosarcoma cells. 3026 96

Previous studies have demonstrated that the C-terminal of E1A binding proteins (CtBPs) influences tumorigenesis by participating in cell signal transduction in various human malignancies. However, the detailed expression patterns of CtBP isoforms in human osteosarcoma (OS) and the molecular mechanisms of CtBP involvement in tumor cell phenotypes requires further investigation. In the present study, the expression patterns of CtBP2 in OS cells and tissues were explored by immunohistochemistry. Fetal osteoblast cells were transfected with a eukaryotic expression plasmid to overexpress CtBP2, and the endogenous CtBP2 in OS cells was silenced via a short hairpin RNA. These transfections were validated and the phosphorylation levels of the JAK1/Stat3 signaling pathway were explored via western blotting. Furthermore, the malignant phenotype of OS cells was evaluated via a Cell Counting Kit-8 assay, cell colony formation assay, cell migration assay and scratch wound healing assay. The results revealed that the expression of CtBP2, but not CtBP1, was upregulated in OS tissue samples and the elevated expression level of CtBP2 was notably associated with distant metastasis. CtBP2 was demonstrated to modulate cell migration and invasion via JAK1/Stat3 signaling pathway in fetal osteoblast cells. In addition, genetic silencing of CtBP2 expression in OS cells notably reduced cell migration abilities and the phosphorylation of the JAK1/Stat3 pathway. In summary, the present studies revealed that the loss of CtBP2 constrained distant metastasis through the JAK1/Stat3 pathway in OS, suggesting that targeting CtBP2 may be a practical anti-tumor approach to prevent OS tumor progression.
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PMID:C-terminal of E1A binding protein 2 promotes the malignancy of osteosarcoma cells via JAK1/Stat3 signaling. 3121 64