Translational autoregulation of thymidylate synthase and dihydrofolate reductase

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

doi:10.2741/1413

Cited by 53 publications

(42 citation statements)

References 35 publications

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“…Therefore, careful evaluation of the redox state and of the substrate availability will be of further need to decipher the molecular roles of enzymatic RBPs. In addition, modulation of RNA-binding function may result from direct competition between RNA and substrates/cofactors as seen with mammalian IRPs, TS and DHFR [15,16]. In that case, RNA binding can only occur when substrates are limiting and/or enzymes are in excess and thus, this could possibly contribute to some of the weaker associations seen between RNA and some of the enzyme-related RBPs in our RIP-Chip experiments.…”

Section: Discussionmentioning

confidence: 94%

“…For instance, TS binds with high affinity to its own 59-UTR near the initiator AUG codon and represses translation [15]. Thereby, mRNA binding sites in TS overlap with the binding sites for its substrates, methylenetetrahydrofolate and dUMP and therefore, mRNA and substrate are in direct competition.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, several metabolic enzymes in mammals have been shown to bind to and regulate mRNA expression (reviewed in [12][13][14][15]). Perhaps best characterized are the iron regulatory proteins (IRP), cytoplasmic aconitases that regulate the translation or stability of several messages depending on cellular iron levels [16].…”

Section: Introductionmentioning

confidence: 99%

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Environmental Regulation of Prions in Yeast

2014

Investigations in Yeast Functional Genomics and Molecular Biology

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Hundreds of RNA-binding proteins (RBPs) control diverse aspects of post-transcriptional gene regulation. To identify novel and unconventional RBPs, we probed high-density protein microarrays with fluorescently labeled RNA and selected 200 proteins that reproducibly interacted with different types of RNA from budding yeast Saccharomyces cerevisiae. Surprisingly, more than half of these proteins represent previously known enzymes, many of them acting in metabolism, providing opportunities to directly connect intermediary metabolism with posttranscriptional gene regulation. We mapped the RNA targets for 13 proteins identified in this screen and found that they were associated with distinct groups of mRNAs, some of them coding for functionally related proteins. We also found that overexpression of the enzyme Map1 negatively affects the expression of experimentally defined mRNA targets. Our results suggest that many proteins may associate with mRNAs and possibly control their fates, providing dense connections between different layers of cellular regulation.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

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Environmental Regulation of Prions in Yeast

2014

Investigations in Yeast Functional Genomics and Molecular Biology

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“…These mechanisms include amplification of TS and altered TS that is not inhibited by FdUMP (39,40). The TS level was reported to be controlled by an autoregulatory feedback mechanism wherein the TS protein interact with and controls the translational efficiency of its own mRNA (41). Disruption of this autoregulatory loop by TS inhibitors leads to up-regulation of TS protein (42).…”

Section: The Effect Of LV and Tpi On The Induction Of Egr-1 And Tsp-1mentioning

confidence: 99%

The role of thymidine phosphorylase in the induction of early growth response protein-1 and thrombospondin-1 by 5-fluorouracil in human cancer carcinoma cells

Akiyama¹

2010

Int J Oncol

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Abstract. Thymidine phosphorylase (TP) is an enzyme involved in reversible conversion of thymidine to thymine. TP is identical to an angiogenic factor, pletelet-derived endothelial cell growth factor (PD-ECGF) and the expression levels of TP in a variety of malignant tumors were higher than the adjacent non-neoplastic tissues. To investigate the molecular basis for the effect of TP on the metabolic process and the anticancer effect of 5-fluorouracil (5-FU), human gastric carcinoma AZ521 cells and epidermoid carcinoma KB cells were transfected with TP cDNA, and AZ521/TP and KB/ TP were cloned. AZ521/TP and KB/TP cells overexpressed TP and were more sensitive to 5-FU than the counterpart parental cells. TPI, a newly synthesized inhibitor for TP (Ki=2.36x10 -9 M), decreased the sensitivity to 5-FU of the TP expressing cells but not of the parental cells. 5-Formyltetrahydrofolate (leucovorin; LV) stabilized the complex of thymidylate synthase (TS) and 5-fluoro-deoxyuridinemonophosphate (FdUMP), increased the sensitivity to 5-FU of TP expressing AZ521 cells, but not of the parental cells. The levels of FdUMP in TP expressing cells were significantly higher than in parental cells and TPI considerably decreased FdUMP to the level comparable to that in the parental cells. 5-FU increased the expression of early growth response protein-1 (Egr-1) and an angiogenesis inhibitor, thrombospondin-1 (TSP-1), in KB/TP cells but only slightly in KB/CV cells, if any. TPI attenuated the induction of Egr-1 and TSP-1 mRNA by 5-FU, while LV increased the expression of Egr-1 and TSP-1 mRNA in KB/TP cells. These findings demonstrate that the TP has a principal role in the production of FdUMP and the enhanced responses to 5-FU by leucovorin in TP-overexpressing KB and AZ521 cells, and FdUMP but not FUTP is implicated in the induction of Egr-1 and TSP-1 in KB cells. IntroductionThymidine phosphorylase (TP) catalyzes the reversible phosphorolysis of thymidine, deoxyuridine, and their analogues to their respective bases and 2-deoxyribose-1-phosphate (1-3). It also catalyzes deoxyribosyltransfer from one deoxynucleotide to another base, to form a second deoxyuridine (4-6). Recent studies showed that TP is expressed in a wide variety of solid tumors (7-13), but the role of TP in tumor proliferation was unknown. We have found that TP is identical to an angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF), and the enzymatic activity of TP is need for the angiogenesis by TP (14-16). TP is also considered to activate some pyrimidine antimetabolites (17-19). 5-Fluorouracil (5-FU) was developed as a potential anti-tumor drug (20), and reportedly activated through three alternative routes. It may be converted to FUMP either directly by orotate phosphoribosyltranferase or by the sequential actions of uridine phosphorylase and uridine kinase. FUMP may be converted to FUDP and then to FUTP, INTERNATIONAL JOURNAL OF ONCOLOGY 36: 1193-1200, 2010 The role of thymidine phosphorylase in the induction of early growth response protein-1...

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“…The enzyme most consistently expressed by the large DNA viruses is thymidine kinase (TK) (2,30). In contrast to that of other nucleosides, de novo synthesis of thymidine requires a single cellular protein that is regulated in a complex manner responsive to TMP pools and other cell cycle cues (63). This is believed to account for why large DNA viruses preferentially encode orthologs of cellular thymidine/thymidylate kinases or in some cases even thymidylate synthases, to ensure adequate thymidine nucleotides for virion replication and to prevent the rapid onset of "thymineless" cell death (1).…”

mentioning

confidence: 99%

Epstein-Barr Virus Thymidine Kinase Is a Centrosomal Resident Precisely Localized to the Periphery of Centrioles

Gill

Kutok

Fingeroth

2007

J Virol

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The thymidine kinase (TK) encoded by Epstein-Barr virus (EBV) differs not only from that of the alphaherpesviruses but also from that of the gamma-2 herpesvirus subfamily. Because cellular location is frequently a determinant of regulatory function, to gain insight into additional role(s) of EBV TK and to uncover how the lymphocryptovirus and rhadinovirus enzymes differ, the subcellular localizations of EBV TK and the related cercopithecine herpesvirus-15 TK were investigated. We show that in contrast to those of the other family members, the gamma-1 herpesvirus TKs localize to the centrosome and even more precisely to the periphery of the centriole, tightly encircling the tubulin-rich centrioles in a microtubule-independent fashion. Centrosomal localization is observed in diverse cell types and occurs whether the protein is expressed independently or in the context of lytic EBV infection. Surprisingly, analysis of mutants revealed that the unique N-terminal domain was not critical for targeting to the centrosome, but rather, peptide sequences located C terminal to this domain were key. This is the first herpesvirus protein documented to reside in the centrosome, or microtubule-organizing center, an amembranous organelle that regulates the structural biology of the cell cycle through control of chromosome separation and cytokinesis. More recently, proteasome-mediated degradation of cell cycle regulatory proteins, production and loading of antigenic peptides onto HLA molecules, and transient homing of diverse virion proteins required for entry and/or egress have been shown to be coordinated at the centrosome. Potential implications of centrosomal localization for EBV TK function are discussed.

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Translational autoregulation of thymidylate synthase and dihydrofolate reductase

Cited by 53 publications

References 35 publications

Environmental Regulation of Prions in Yeast

Environmental Regulation of Prions in Yeast

The role of thymidine phosphorylase in the induction of early growth response protein-1 and thrombospondin-1 by 5-fluorouracil in human cancer carcinoma cells

Epstein-Barr Virus Thymidine Kinase Is a Centrosomal Resident Precisely Localized to the Periphery of Centrioles

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