Thymidylate synthase as a translational regulator of cellular gene expression

Li, Jun; Schmitz, John C.; Lin, Xiukun; Tai, Ningwen; Wu, Yan; Farrell, Michael; Bailly, Michelle; Chen, Tian Min; Chu, Edward

doi:10.1016/s0925-4439(02)00080-7

Cited by 107 publications

(94 citation statements)

References 63 publications

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“…These results indicate that the TS-and/or p53-high phenotype as determined by immunohistochemistry is a strong predictor of the resistance to S-1/cisplatin chemotherapy. Reportedly, TS forms a ribonucleoprotein complex with the p53 mRNA and the functional consequence of the binding is translational repression (Liu et al, 2002). In the lesions showing p53-low but TShigh phenotype (observed in five lesions of the nonresponders but in none of the responders), thus, TS may play a critical role in regulating the process of apoptosis through its regulatory effects on expression of p53.…”

Section: Discussionmentioning

confidence: 99%

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Immunostaining of thymidylate synthase and p53 for predicting chemoresistance to S-1/cisplatin in gastric cancer

et al. 2007

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High expression of thymidylate synthase (TS) and inactivation of p53 are allegedly associated with chemoresistance. The authors evaluated TS and p53 expression in gastric cancer treated with neoadjuvant S-1/cisplatin chemotherapy. Paraffin sections of pretreatment biopsy and surgical specimens from 41 gastric cancers were immunostained for TS and p53 protein after appropriate antigen retrieval. Fifty-one cases without neoadjuvant chemotherapy were also studied. In the pretreatment biopsies, high expression of TS was seen in 8% of the histologic responders, in 28% of the nonresponders and in 31% of the controls. High expression of p53 was observed in 56% of the nonresponders, but in 8% of the responders and in 29% of the controls (Po0.01 and Po0.05, respectively). The TS-and/or p53-high phenotype was seen in 76% of the nonresponders and in 54% of the controls, but in 8% of the responders (Po0.0001 and Po0.005, respectively). The data of the surgical specimens were consistent with those of the pretreatment biopsies. These results suggest that immunostaining for TS and p53 protein is useful for pretreatment selection of gastric cancer patients unresponsive to S-1/cisplatin chemotherapy.

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Section: Discussionmentioning

confidence: 99%

“…There is evidence that TS forms a ribonucleoprotein complex with p53 mRNA (Liu et al, 2002). It is thereby suggested that TS may play a critical role in regulating the cell cycle and the process of apoptosis through its regulatory effects on the expression of p53.…”

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confidence: 99%

Immunostaining of thymidylate synthase and p53 for predicting chemoresistance to S-1/cisplatin in gastric cancer

et al. 2007

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“…Unlike the protein response, hypoxia has been shown to have little effect on HIF-1a transcription in cell culture (Giaccia et al, 2003). Similarly, TS is mainly controlled at the translational level (Liu et al, 2002), which provides an energyefficient, rapid response to cellular stresses. However, we noted a sustained effect of ischaemia on TS and HIF-1a mRNA levels, highlighting the need for rapid preservation following tissue extirpation.…”

Section: Discussionmentioning

confidence: 99%

The effect of surgically induced ischaemia on gene expression in a colorectal cancer xenograft model

et al. 2005

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Delays in tissue fixation following tumour vascular clamping and extirpation may adversely affect subsequent protein and mRNA analysis. This study investigated the effect of surgically induced ischaemia in a xenograft model of a colorectal cancer on the expression of a range of prognostic, predictive, and hypoxic markers, with a particular emphasis on thymidylate synthase. Vascular occlusion of human tumour xenografts by D-shaped metal clamps permitted defined periods of tumour ischaemia. Alterations in protein expression were measured by immunohistochemistry and spectral imaging, and changes in mRNA were measured by reverse transcriptase -polymerase chain reaction. Thymidylate synthase expression decreased following vascular occlusion, and this correlated with cyclin A expression. A similar reduction in dihydropyrimidine dehydrogenase was also seen. There were significant changes in the expression of several hypoxic markers, with carbonic anhydrase-9 showing the greatest response. Gene transcriptional levels were also noted to change following tumour clamping. In this xenograft model, surgically induced tumour ischaemia considerably altered the gene expression profiles of several prognostic and hypoxic markers, suggesting that the degree of tumour ischaemia should be minimised prior to tissue fixation.

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“…9 Second, the translation of TS mRNA is negatively autoregulated by the binding of TS enzyme to its mRNA. [10][11][12] This binding is disrupted when TS substrates or inhibitors are bound to the enzyme, leading to relief of translational repression and increased production of the enzyme. Finally, long-term exposure to TS inhibitors selects for cells in which TS is highly overproduced as a result of TS gene amplification.…”

Section: Introductionmentioning

confidence: 99%

Stable inhibition of human thymidylate synthase expression following retroviral introduction of an siRNA gene

et al. 2005

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Thymidylate synthase (TS) is an essential enzyme that synthesizes thymidylic acid in the de novo biosynthetic pathway. Inhibiting TS enzyme activity with substrate or cofactor analogs leads to inhibition of DNA replication and cell death. For this reason, TS is an important target enzyme for cancer chemotherapeutic drugs. We describe an alternative approach to reducing cellular TS enzyme activity using short interfering RNA (siRNA) technology to lower TS mRNA levels. Plasmids that direct the synthesis of siRNAs that target nucleotides 898-916 and 965-983 (relative to the A of the translational start codon) of human TS mRNA were highly effective at reducing TS enzyme levels in transient transfection assays. Infection of HeLa cells with retroviruses that contain the effective siRNA genes led to a stable 80-95% reduction of TS enzyme and mRNA. A similar percent reduction in TS expression was observed in a cell line that overproduces TS enzyme 100-fold due to TS gene amplification. Cells that exhibited the greatest reduction in TS enzyme level grew poorly in medium that lacked thymidine. These observations suggest that siRNA approaches may provide an alternative therapeutic strategy to reduce TS enzyme levels.

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Thymidylate synthase as a translational regulator of cellular gene expression

Cited by 107 publications

References 63 publications

Immunostaining of thymidylate synthase and p53 for predicting chemoresistance to S-1/cisplatin in gastric cancer

Immunostaining of thymidylate synthase and p53 for predicting chemoresistance to S-1/cisplatin in gastric cancer

The effect of surgically induced ischaemia on gene expression in a colorectal cancer xenograft model

Stable inhibition of human thymidylate synthase expression following retroviral introduction of an siRNA gene

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