ArticleThe Journal of biological chemistry2015
Dihydrofolate Reductase and Thymidylate Synthase Transgenes Resistant to Methotrexate Interact to Permit Novel Transgene Regulation.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 38 citations in OpenAlex.
- CRISPR/methotrexate-integrated strategy for TCR-T cell engineering with reduced chromosome 14 loss.Molecular therapy. Methods & clinical development · 2025Article
- Investigation of 6-thioguanine as a strategy to overcome methotrexate resistance in a mouse model of leptomeningeal carcinomatosis.Journal of neuro-oncology · 2025Article
- Combinatorial QM and MD in silico design of natural product-based DHFR inhibitors.Scientific reports · 2025Article
- Combating Methotrexate Resistance in Cancer Treatment: A Review on Navigating Pathways and Enhancing Its Efficacy With Fat-Soluble Vitamins.Scientifica · 2025Review
- Astaxanthin Co-treatment with Low Dose Methotrexate Increases the Cell Cycle Arrest and Ameliorates the Methotrexate-induced Inflammatory Response in NALM-6.International journal of molecular and cellular medicine · 2024Article
- Sexual Dimorphism of the Mouse Plasma Metabolome Is Associated with Phenotypes of 30 Gene Knockout Lines.Metabolites · 2023Article
- Modulation of DNA methylation by one-carbon metabolism: a milestone for healthy aging.Nutrition research and practice · 2023Review
- Resistance Mechanisms in Pediatric B-Cell Acute Lymphoblastic Leukemia.International journal of molecular sciences · 2022Review
- The antimicrobial drug pyrimethamine inhibits STAT3 transcriptional activity by targeting the enzyme dihydrofolate reductase.The Journal of biological chemistry · 2022Article
- Lectin galactoside-binding soluble 3 binding protein mediates methotrexate resistance in choriocarcinoma cell lines.Bioengineered · 2022Article
- Diagnosis, prognosis and treatment of primary central nervous system lymphoma in the elderly population (Review).International journal of oncology · 2021Review
- Incorporation of methotrexate into coconut oil nanoemulsion potentiates its antiproliferation activity and attenuates its oxidative stress.Drug delivery · 2020Article
- The evaluation of red blood cell folate and methotrexate levels during protocol M in childhood acute lymphoblastic leukemia.BMC cancer · 2020Article
- GSEA-assisted gene signatures valid for combinations of prognostic markers in PCNSL.Scientific reports · 2020Article
- Differential expression of N-linked oligosaccharides in methotrexate-resistant primary central nervous system lymphoma cells.BMC cancer · 2019Article
- Cell-type-specific sensitivity of bortezomib in the methotrexate-resistant primary central nervous system lymphoma cells.International journal of clinical oncology · 2019Article
- Differential expression of individual transcript variants of PD-1 and PD-L2 genes on Th-1/Th-2 status is guaranteed for prognosis prediction in PCNSL.Scientific reports · 2019Article
- Article
- Ribosome Mediated Quinary Interactions Modulate In-Cell Protein Activities.Biochemistry · 2017Article
- Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Methotrexate (MTX) is an anti-folate that inhibits de novo purine and thymidine nucleotide synthesis. MTX induces death in rapidly replicating cells and is used in the treatment of multiple cancers. MTX inhibits thymidine synthesis by targeting dihydrofolate reductase (DHFR) and thymidylate synthase (TYMS). The use of MTX to treat cancer also causes bone marrow suppression and inhibits the immune system. This has led to the development of an MTX-resistant DHFR, DHFR L22F, F31S (DHFR(FS)), to rescue healthy cells. 5-Fluorouracil-resistant TYMS T51S, G52S (TYMS(SS)) is resistant to MTX and improves MTX resistance of DHFR(FS) in primary T cells. Here we find that a known mechanism of MTX-induced increase in DHFR expression persists with DHFR(FS) and cis-expressed transgenes. We also find that TYMS(SS) expression of cis-expressed transgenes is similarly decreased in an MTX-inducible manner. MTX-inducible changes in DHFR(FS) and TYMS(SS) expression changes are lost when both genes are expressed together. In fact, expression of the DHFR(FS) and TYMS(SS) cis-expressed transgenes becomes correlated. These findings provide the basis for an unrecognized post-transcriptional mechanism that functionally links expression of DHFR and TYMS. These findings were made in genetically modified primary human T cells and have a clear potential for use in clinical applications where gene expression needs to be regulated by drug or maintained at a specific expression level. We demonstrate a potential application of this system in the controlled expression of systemically toxic cytokine IL-12.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.