Regulation of Thymidylate Synthase Gene Expression in Growth-Stimulated Cells

1994 ◽  
pp. 141-147 ◽  
Author(s):  
Lee F. Johnson
Keyword(s):  
Gene Expression ◽  
Thymidylate Synthase

scholarly journals Murine Cytomegalovirus Stimulates Cellular Thymidylate Synthase Gene Expression in Quiescent Cells and Requires the Enzyme for Replication

2000 ◽  
Vol 74 (11) ◽  
pp. 4979-4987 ◽  
Author(s):  
Giorgio Gribaudo ◽  
Ludovica Riera ◽  
David Lembo ◽  
Marco De Andrea ◽  
Marisa Gariglio ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thymidylate Synthase ◽  
De Novo ◽  
Present Report ◽  
Murine Cytomegalovirus ◽  
Mcmv Infection ◽  
Quiescent Cells ◽  
Cellular Genes ◽  
Efficient Replication ◽  
Responsive Element

ABSTRACT Herpesviruses accomplish DNA replication either by expressing their own deoxyribonucleotide biosynthetic genes or by stimulating the expression of the corresponding cellular genes. Cytomegalovirus (CMV) has adopted the latter strategy to allow efficient replication in quiescent cells. In the present report, we show that murine CMV (MCMV) infection of quiescent fibroblasts induces both mRNA and protein corresponding to the cellular thymidylate synthase (TS) gene, which encodes the enzyme that catalyzes the de novo synthesis of thymidylic acid. The increase in TS gene expression was due to an increase in gene transcription, since the activity of a reporter gene driven by the mouse TS promoter was induced following MCMV infection. Mutagenesis of the potential E2F-responsive element immediately upstream from the TS essential promoter region abolished the virus-mediated stimulation of the TS promoter, suggesting that the transactivating activity of MCMV infection was E2F dependent. Cotransfection experiments revealed that expression of the viral immediate-early 1 protein was sufficient to mediate the increase in TS promoter activity. Finally, MCMV replication and viral DNA synthesis were found to be inhibited by ZD1694, a quinazoline-based folate analog that inhibits TS activity. These results demonstrate that upregulation of cellular TS expression is required for efficient MCMV replication in quiescent cells.

Effect of 5-Fluorouracil on the Regulation of Zebrafish Thymidylate Synthase Gene Expression

2013 ◽  
Vol 641-642 ◽  
pp. 732-735
Author(s):  
Chun Xia Song ◽  
Qian Zhang ◽  
Yu Liang Xiao
Keyword(s):  
Gene Expression ◽  
Thymidylate Synthase ◽  
De Novo ◽  
Mrna Level ◽  
Translation System ◽  
Transcriptional Level ◽  
Important Target ◽  
Reticulocyte Lysate ◽  
First Time ◽  
Translational Level

Thymidylate synthase (TS) is an important target in cancer therapy, which is a folate-dependent enyme, catalyzing the de novo synthesis of dUMP. In this report, the effect of 5-flurorouracil (5-FU) on the regulation of TS gene expression was estimated in zebrafish. The results showed 5-FU could significantly increase the TS expression in zebrafish embryos. However, TS mRNA level were remained unchanged. To determine the effect of 5-FU and 5-FdUMP on translation of TS mRNA, a rabbit reticulocyte lysate translation system was used. Addition of 5-FU, not inhibited the translation of TS mRNA. While addition of 5-FdUMP, completely repressed the translation of TS mRNA. Therefore, induced expression of thymidylate synthase by 5-FU in zebrafish occurred in translational level, not in transcriptional level. The findings demonstrated that zebrafish TS protein was able to bind to its own cogate mRNA and the 5-FU regulated TS in the translational level. This is the first time to confirm that the regulation of TS is affected by TS and its cognant mRNA interaction in the whole animal level.

Colorectal Carcinomas with Microsatellite Instability Display Increased Thymidylate Synthase Gene Expression Levels

2007 ◽  
Vol 6 (10) ◽  
pp. 720-727 ◽  
Author(s):  
Elisabeth Odin ◽  
Yvonne Wettergren ◽  
Staffan Nilsson ◽  
Göran Carlsson ◽  
Bengt Gustavsson
Keyword(s):  
Gene Expression ◽  
Microsatellite Instability ◽  
Thymidylate Synthase ◽  
Colorectal Carcinomas ◽  
Expression Levels ◽  
Gene Expression Levels

223 Increased thymidylate synthase gene expression in metastatic melanoma

1995 ◽  
Vol 31 ◽  
pp. S49
Author(s):  
M. Kesomaa ◽  
A. Jekunen ◽  
T. Vlaykova ◽  
V-M. Wasenius ◽  
K.J.A. Kairemo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metastatic Melanoma ◽  
Thymidylate Synthase

Thymidylate synthase (TS) gene expression in patients with ALK positive (+) non-small cell lung cancer (NSCLC): Implications for therapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7582-7582 ◽  
Author(s):  
David R. Gandara ◽  
Eric Huang ◽  
Sonal Desai ◽  
Philip C. Mack ◽  
Laurel Beckett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thymidylate Synthase ◽  
Predictive Biomarker ◽  
Rt Pcr ◽  
Kras Mutations ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Report Analysis ◽  
Increased Sensitivity ◽  
Alk Positive

7582 Background: ALK+ NSCLC represents a molecular target-defined patient population highly responsive to the ALK inhibitor crizotinib. Previous reports have also suggested increased sensitivity of ALK+ NSCLC to the chemotherapeutic agent pemetrexed. Thymidylate synthase (TS) is a candidate predictive biomarker for pemetrexed activity. Here we report analysis of the Response Genetics Inc. (RGI) database for this association and implications for therapy. Methods: ALK fusion was identified by a novel RT-PCR assay (Danenberg et al: ASCO 2010). For TS, RNA from microdissected formalin-fixed paraffin-embedded tumors was analyzed as previously described, reported as the ratio of gene expression to β-actin. For reference, a TS level <2.33 is the cutpoint for sensitivity. Results: TS levels were available from 63 ALK+ patients and 1,698 ALK- control lung adenocarcinoma patients. All ALK+ patients had adenocarcinomas without EGFR or KRAS mutations. Median age: 59.0 (range 33-88), gender (male/female) 32/31 (51%/49%). Median TS RNA level in ALK+ patients was 2.02, range (0.55-19.44), and in ALK- patients was 3.32 (0.36-53.51), p<0.0001 (Mann-Whitney test). The majority of ALK+ patients (N=43, 68%) had a TS level <2.33 cutpoint, compared to only 32% of ALK- patients (N=551, p<0.0001). Conclusions: This analysis demonstrates relatively low TS gene expression in ALK+ patient tumors as determined by RT-PCR. These data provide a mechanism of action supportive of pemetrexed sensitivity for ALK+ NSCLC. [Table: see text]

Thymidylate synthase (TS) expression as a prognostic molecular marker in stage II/III colon cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3577-3577
Author(s):  
Dirk Klingbiel ◽  
Edoardo Missiaglia ◽  
Pu Yan ◽  
Sabine Tejpar ◽  
Arnaud Roth ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thymidylate Synthase ◽  
Copy Number ◽  
Cox Regression ◽  
Gene Copy Number ◽  
Tumor Grade ◽  
Gene Copy ◽  
Allelic Loss ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

3577 Background: Studies on the association between colorectal cancer (CC) outcome and thymidylate synthase expression have provided inconsistent results. In this study we attempted to resolve the issue by assessing the associations between TS expression and outcome in a population of primary CC patients (pts), who after resection were randomized to 5-FU/FA vs. FOLFIRI adjuvant therapy. Methods: Immunohistochemical staining for TS protein was successfully performed for 1211 pts in the PETACC3 trial. TS immunoreactivity was scored as high expression (≥75% positive) and low expression (<75% positive). Gene expression respectively copy number data were available for 853 respectively 306 of these samples. Twelve single nucleotide polymorphisms (SNPs) close to the TYMS gene were assessed in 923 pts. Association of variables with relapse-free (RFS) and overall survival (OS) was assessed using Cox regression models. Results: High TS expression and RNA level were strongly associated (log fold change 0.65, p<0.001). Both were significantly higher in proximal CC. As expected, both were associated with other characteristics of proximal CC: MSI, BRAF mutation, high tumor grade. RNA was significantly correlated with gene copy number, distal CC showing more frequent allelic loss. Three SNPs were associated with gene expression which was validated in data from the 1000 genomes project, but none with survival. High TS expression was more strongly associated with better OS in pts receiving FOLFIRI (HR 0.4, 95% CI 0.3–0.6, p<0.001), than 5-FU/FA (HR 0.8, 95% CI 0.5–1.1, p=0.13), with a significant interaction (p=0.05). Similar results were observed for RFS (HR 0.5, p<0.001 vs. HR 0.7, p=0.07; interaction p=0.11). TS expression is still highly prognostic in multivariate models adjusting for factors associated with risk or proximal tumors in FOLFIRI treated pts (OS: HR 0.5, p=0.008; RFS: HR 0.6, p=0.02), but not in F-FU/FA treated pts (OS and RFS: HR=1, p=1). Conclusions: TS expression is lower in distal CC, partly due to deletion of the TYMS locus. Pts with high TS expression have longer RFS and OS, notably when treated with FOLFIRI. For these pts addition of irinotecan to 5-FU/FA adjuvant chemotherapy might be considered. Clinical trial information: NCT00026273.

Histone deacetylase inhibitors suppress thymidylate synthase gene expression and synergize with the fluoropyrimidines in colon cancer cells

2009 ◽  
Vol 125 (2) ◽  
pp. 463-473 ◽  
Author(s):  
William Fazzone ◽  
Peter M. Wilson ◽  
Melissa J. LaBonte ◽  
Heinz-Josef Lenz ◽  
Robert D. Ladner
Keyword(s):  
Gene Expression ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Histone Deacetylase ◽  
Thymidylate Synthase ◽  
Histone Deacetylase Inhibitors ◽  
Colon Cancer Cells

scholarly journals High thymidylate synthase gene expression predicts poor outcome after resection of hepatocellular carcinoma

PLoS ONE ◽  
2019 ◽  
Vol 14 (7) ◽  
pp. e0219469 ◽  
Author(s):  
David B. Donner ◽  
Eric K. Nakakura ◽  
Alan P. Venook ◽  
Heinz-Josef Lenz ◽  
Wu Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Thymidylate Synthase ◽  
Poor Outcome
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