A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance.

A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Research Abstract Details 

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A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Abstract Text:

Prasun J Mishra,Rita Humeniuk,Pravin J Mishra,Giuseppe S A Longo-Sorbello,Debabrata Banerjee,Joseph R Bertino,

MicroRNAs are predicted to regulate approximately 30% of all human genes by targeting sequences in their 3' UTR. Polymorphisms in 3' UTR of several genes have been reported to affect gene expression, but the mechanism is not fully understood. Here, we demonstrate that 829C-->T, a naturally occurring SNP, near the miR-24 binding site in the 3' UTR of human dihydrofolate reductase (DHFR) affects DHFR expression by interfering with miR-24 function, resulting in DHFR overexpression and methotrexate resistance. miR-24 has a conserved binding site in DHFR 3' UTR. DHFR with WT and 3' UTR containing the 829C-->T mutation were expressed in DG44 cells that lack DHFR. Overexpression of miR-24 in cells with WT DHFR resulted in down-regulation of DHFR protein, whereas no effect on DHFR protein expression was observed in the mutant 3' UTR-expressing cells. Inhibition of endogenous miR-24 with a specific inhibitor led to up-regulation of DHFR in WT and not in mutant cells. Cells with the mutant 3' UTR had a 2-fold increase in DHFR mRNA half-life, expressed higher DHFR mRNA and DHFR protein, and were 4-fold more resistant to methotrexate as compared with WT cells. SNP-829C-->T, therefore, leads to a decrease in microRNA binding leading to overexpression of its target and results in resistance to methotrexate. We demonstrate that a naturally occurring miRSNP (a SNP located at or near a microRNA binding site in 3' UTR of the target gene or in a microRNA) is associated with enzyme overproduction and drug resistance.

A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Publishing Authors By Initials

PJ Mishra,R Humeniuk,PJ Mishra,GS Longo-Sorbello,D Banerjee,JR Bertino,

For similar enzymes and coenzymes: enzymes: oxidoreductases: oxidoreductases acting on ch-nh group donors: tetrahydrofolate dehydrogenase research abstracts see: enzymes and coenzymes: enzymes: oxidoreductases: oxidoreductases acting on ch-nh group donors: tetrahydrofolate dehydrogenase research

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A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Proceedings of the National Academy of Sciences of

VOLUME: 104

Page Numbers: 13513-8

Journal Abbreviation: Proc. Natl. Acad. Sci. U.S.A.

ISSN: 0027-8424

DAY: 8

MONTH: 08

YEAR: 2007

A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7505876

A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Keywords Mesh Terms:

KEYWORDS: Tetrahydrofolate Dehydrogenase

MESH TERMS: genetics

Chemical & Substance for Abstract: A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Information

Substance Name: Tetrahydrofolate Dehydrogenase

Registry Number: EC 1.5.1.3

Grant and Affiliation Information for A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance.

AFFILIATION: Department of Pharmacology, Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903, USA.

Country: United States

AGENCY: United States NCI

GRANT: CA0810

ACRONYM: CA

MEDLINETA: Proc Natl Acad Sci U S A

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