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)

Polo-like kinase 2 (Plk2) is a member of the serine/threonine protein kinase family involved in cell-cycle regulation and cellular response to stresses. It is of great interest to investigate the molecular mechanisms that control the expression of Plk2. Here, using real-time PCR and Western blot assays, we show that trichostatin A (TSA), a histone deacetylase inhibitor, upregulated Plk2 mRNA and protein expression in the human osteosarcoma MG-63 cell line. Luciferase activity analysis of the truncated Plk2 promoter indicated that the region from -1220 to -830 of the Plk2 promoter was sensitive to TSA. Moreover, using the electrophoresis mobility shift assay and chromatin immunoprecipitation assay, we identified two GATA-1 responsive elements at positions -1051 and -949, to which GATA-1 binding was enhanced by TSA under in vitro and in vivo conditions. Immunoprecipitation and Western blot showed that the levels of acetylated GATA-1 were increased with TSA in MG-63 cells, consistent with their binding affinities to the GATA-1 responsive elements. In summary, these data demonstrate that acetylation plays a crucial role in Plk2 expression and acetylation of GATA-1 by TSA treatment may upregulate their DNA-binding affinities, resulting in the activation of Plk2 promoter. These results may contribute to the understanding of the molecular mechanism of Plk2 regulation.
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PMID:Upregulation of Polo-like kinase 2 gene expression by GATA-1 acetylation in human osteosarcoma MG-63 cells. 2213 23

The polo-like kinase (PLKs) family, consisting of five known members, are key regulators of important cell cycle processes, which include mitotic entry, centrosome duplication, spindle assembly, and cytokinesis. The PLKs have been implicated in a variety of cancers, such as hepatocellular carcinoma (HCC), with PLK1 typically overexpressed and PLKs 2-5 often downregulated. Altered expression of the PLKs in malignancy is often correlated with aberrant promoter methylation. Epigenetic marks are dynamic and can be modified in response to external environmental stimuli. The aim of our study was to determine if oxidative stress, a common feature of solid tumours, would induce changes to the promoter methylation of the PLKs resulting in changes in expression. We examined the promoter methylation status via MSP and subsequent expression levels of the PLK family members under exposure to hypoxic conditions or reactive oxygen species (ROS). Interestingly, murine embryonic fibroblasts exposed to hypoxia and ROS displayed significant hypermethylation of Plk1 and Plk4 promoter regions post treatment. Corresponding proteins were also depleted by 40% after treatment. We also examined the HCC-derived cell lines HepG2 and Hep3B and found that for PLK1 and PLK4, the increase in hypermethylation was correlated with the presence of functional p53. In p53 wild-type cells, HepG2, both PLK1 and PLK4 were repressed with treatment, while in the p53 null cell line, Hep3B, PLK4 protein was elevated in the presence of hypoxia and ROS. This was also the case for ROS-treated, p53 null, osteosarcoma cells, Saos-2, where the PLK4 promoter became hypomethylated and protein levels were elevated. Our data supports a model in which the PLKs are susceptible to epigenetic changes induced by microenvironmental cues and these modifications may be p53-dependent. This has important implications in HCC and other cancers, where epigenetic alterations of the PLKs could contribute to tumourigenesis and disease progression.
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PMID:p53-Dependent and cell specific epigenetic regulation of the polo-like kinases under oxidative stress. 2449 22

Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. Existing treatment options and surgical intervention are unable to effectively manage this tumor. Therefore, novel mechanism-based targets and strategies need to be rationally established to strive for improvement in the survival of patients diagnosed with osteosarcoma. The serine/threonine kinases Polo-like kinase (Plk) 1 is a key regulator of cell division in eukaryotic cells. Plk1 gene and protein expression has been proposed as a new prognostic marker for many types of malignancies, and Plk1 is a potential target for cancer therapy. In this review, we shall discuss the studies which indicate that Plk1 could be an excellent target for the treatment of osteosarcoma.
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PMID:Polo-like kinase 1 as a potential therapeutic target for osteosarcoma. 2534 14

TAp73, a member of the p53 tumor suppressor family, can substitute for p53 function, especially in p53-null and p53-mutant cells. However, TAp73 enrichment and phosphorylation change its transcriptional activity. Previously, we found that the antitumor function of TAp73 was reactivated by dephosphorylation. Polo-like kinase 2 (PLK2) plays an important role in bone development. Using a biological information database and phosphorylation prediction software, we hypothesized that PLK2 phosphorylates TAp73 and inhibits TAp73 function in osteosarcomas. Actually,we determined that PLK2 physically binds to and phosphorylates TAp73 when TAp73 protein abundance is up-regulated by cisplatin. PLK2-phosphorylated TAp73 at residue Ser48 within the TA domain; phosphorylation of TAp73 was abolished by mutating this residue. Moreover, PLK2 inhibition combined with cisplatin treatment in osteosarcoma Saos2 cells up-regulated p21 and puma mRNA expression to a greater extent than cisplatin treatment alone. Inhibiting PLK2 in TAp73-enriched Saos2 cells resulted in inhibited cell proliferation, increased apoptosis, G1 phase arrest, and decreased cell invasion. However, these changes did not occur in TAp73 knockdown Saos2 cells. In conclusion, these findings reveal a novel PLK2 function in the phosphorylation of TAp73, which prevents TAp73 activity in osteosarcoma cells. Thereby, this research provides an insight into the clinical treatment of malignant tumors overexpressing TAp73.
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PMID:PLK2 phosphorylates and inhibits enriched TAp73 in human osteosarcoma cells. 2662 70