Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.21 (thymidine kinase)
 7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycoprotein 130 (gp130), a shared component of all the receptors for the interleukin-6 cytokine family, transduces cytokine signals in part by activating latent cytoplasmic signal transducers and activators of transcription (STATs). STATs subsequently translocate into the nucleus and stimulate gene expression. In the studies reported here, the 5'-flanking region of the human gp130 gene was isolated and the transcription initiation sites were mapped. To demonstrate that the isolated DNA fragment contained a functional promoter, a plasmid construct containing 2433 base pairs of the gp130 5'-flanking region, inserted upstream from the firefly luciferase gene, was transiently transfected into HepG2 hepatoma cells. The construct exhibited constitutive promoter activity. In addition, a 5-h treatment with interleukin-6 or oncostatin M stimulated the activity of this promoter severalfold. Localization of the cytokine response element by 5'-deletion analysis and site-directed mutagenesis revealed a cis-acting binding site for activated STAT complexes. Furthermore, DNA binding analysis demonstrated that this element binds activated STAT1 and STAT3 homo- and heterodimers. This STAT-binding element was sufficient to confer cytokine stimulation to a minimal herpesvirus thymidine kinase promoter. These results establish that the DNA fragment we have isolated contains the human gp130 promoter and that interleukin-6 type cytokines may influence the activity of this promoter via activated STATs.
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PMID:Isolation and characterization of the human gp130 promoter. Regulation by STATS. 916 75

Cytokine oncostatin M (OM) exerts growth-inhibitory and differentiative effects on breast cancer cells. Previously we showed that the transcription from the p53 gene in breast cancer cells was down regulated by OM. To elucidate the molecular mechanisms underlying the OM effect on p53 transcription, in this study, we dissected the p53 promoter region and analysed the p53 promoter activity in breast tumor cells. We showed that treatment of MCF-7 cells with OM induced a dose- and time-dependent suppression of p53 promoter activity. The p53 promoter activity was decreased to 35% of control at 24 h and further decreased to 20% at 48 h by OM at concentrations of 5 ng/ml and higher. Deletion of the 5'-flanking region of the p53 promoter from -426 to -97 did not affect the OM effect. However, further deletion to -40 completely abolished the repressive effect of OM. The p53 promoter region -96 to -41 contains NF-kappaB and c-myc binding sites, and a newly identified UV-inducible element PE21. Mutations to disrupt NF-kappaB binding or c-myc binding to the p53 promoter decreased the basal promoter activity without affecting the OM-mediated suppression, whereas mutation at the PE21 motif totally abolished the OM effect. We further demonstrated that insertion of PE21 element upstream of the thymidine kinase minimal promoter generated an OM response analogous to that of the p53 promoter. Finally, we detected the specific binding of a nuclear protein with a molecular mass of 87 kDa to the PE21 motif. Taken together, we demonstrate that OM inhibits the transcription of the p53 gene through the PE21 element. Thus, the PE21 element is functionally involved in p53 transcription regulated by UV-induction and OM suppression.
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PMID:The critical role of the PE21 element in oncostatin M-mediated transcriptional repression of the p53 tumor suppressor gene in breast cancer cells. 1178 35

Our previous studies have shown that treatment of MCF-7 breast cancer cells with cytokine oncostatin M (OM) results in a growth arrest and a concurrent decrease in p53 expression. It remains to be determined whether these two important events are directly connected, as changes in p53 protein levels can lead to variable biological outcomes. In this study we have generated stable cell lines (MCF7-ptsp53) that express p53Val135 a p53 temperature-sensitive mutant. We demonstrate that overexpression of the wildtype (wt) p53 at permissive temperature in MCF7-ptsp53 cells leads to growth arrest at the G2-M phase of the cell cycle. Inhibition of endogenous p53 function with the expression of mutant p53 protein at non-permissive temperature did not affect the OM-induced G1 cell cycle arrest. Microarray studies were further carried out to identify p53- and OM-regulated genes that mediate the G2/M or G1 cell cycle arrest. We show that the expression of p21 was upregulated and expressions of cdc2, cyclin B2 and protein regulator of cytokinesis 1 (PRC1) were suppressed by overexpression of the wt p53 in MCF7-ptsp53 cells at the permissive temperature. In contrast, OM treatment caused coordinate changes of mRNA expression of several cell cycle components including c/EBPdelta, cdc20, and thymidine kinase 1 (TK1) that mainly affect G1-S phase transition. All together, our results suggest that the downregulation of p53 transcription may be involved in some other cellular changes induced by OM but it is not directly connected to the antiproliferative activity of OM per se.
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PMID:Molecular characterization of oncostatin M-induced growth arrest of MCF-7 cells expressing a temperature-sensitive mutant of p53. 1288 96