Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.5.4.4 (
adenosine deaminase
)
5,136
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Dihydrofolate reductase
(
DHFR
) plays a key role in folate metabolism and is a target molecule of methotrexate. An increase in the cellular expression level of
DHFR
is one of the mechanisms of tumor resistance to methotrexate. The present study investigated the possibility that adenosine-to-inosine RNA editing, which causes nucleotide conversion by
adenosine deaminase
acting on RNA (ADAR) enzymes, might modulate
DHFR
expression. In human breast adenocarcinoma-derived MCF-7 cells, 26 RNA editing sites were identified in the 3'-UTR of
DHFR
. Knockdown of ADAR1 decreased the RNA editing levels of
DHFR
and resulted in a decrease in the
DHFR
mRNA and protein levels, indicating that ADAR1 up-regulates
DHFR
expression. Using a computational analysis, miR-25-3p and miR-125a-3p were predicted to bind to the non-edited 3'-UTR of
DHFR
but not to the edited sequence. The decrease in
DHFR
expression by the knockdown of ADAR1 was restored by transfection of antisense oligonucleotides for these miRNAs, suggesting that RNA editing mediated up-regulation of
DHFR
requires the function of these miRNAs. Interestingly, we observed that the knockdown of ADAR1 decreased cell viability and increased the sensitivity of MCF-7 cells to methotrexate. ADAR1 expression levels and the RNA editing levels in the 3'-UTR of
DHFR
in breast cancer tissues were higher than those in adjacent normal tissues. Collectively, the present study demonstrated that ADAR1 positively regulates the expression of
DHFR
by editing the miR-25-3p and miR-125a-3p binding sites in the 3'-UTR of
DHFR
, enhancing cellular proliferation and resistance to methotrexate.
...
PMID:A-to-I RNA Editing Up-regulates Human Dihydrofolate Reductase in Breast Cancer. 2818 87
