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:1.5.1.3 (
dihydrofolate reductase
)
5,819
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The relationship between loss of functional p53 and human reduced folate carrier (hRFC) levels and function was examined in REH lymphoblastic leukemia cells, which express wild type p53, and in p53-null K562 cells (K562(pTet-on/p53)) engineered to express wild type p53 under control of a tetracycline-inducible promoter. Activation of p53 in REH cells by treatment with daunorubicin was accompanied by decreased ( approximately 5-fold) levels of hRFC transcripts and methotrexate transport. Treatment of K562(pTet-on/p53) cells with doxycycline resulted in a dose-dependent expression of p53 protein and transcripts, increased p21 protein, decreased
dihydrofolate reductase
, and G(1) arrest with decreased numbers of cells in S-phase. p53 induction was accompanied by up to 3-fold decreases in hRFC transcripts transcribed from the upstream hRFC-B promoter and similar losses of hRFC protein and methotrexate uptake capacity. Expression of
p15
in an analogous inducible system in K562 cells resulted in a nearly identical decrease of S-phase cells and
dihydrofolate reductase
without effects on hRFC levels or activity. When the hRFC-B promoter was expressed as full-length and basal promoter-luciferase reporter constructs in K562(pTet-on/p53) cells, induction of p53 with doxycycline resulted in a 3-fold loss of promoter activity, which was reversed by cotransfection with a trans-dominant-negative p53. These studies show that wild type p53 acts as a repressor of hRFC gene expression, via a mechanism that is independent of its effects on cell cycle progression.
...
PMID:Repression of human reduced folate carrier gene expression by wild type p53. 1110 43
The downstream effects of
p15
and p16 gene deletions and loss of transcripts on
dihydrofolate reductase
(
DHFR
) were examined in 63 B-precursor (BP) acute lymphoblastic leukaemia (ALL) samples.
p15
and/or p16 gene deletions were seen in 6% and 8%, respectively, of BP-ALL samples; however, losses of
p15
and/or p16 transcripts were seen in 26 out of 63 (41%) samples. Loss of
p15
transcripts (36.5%) exceeded that for p16 (17.5%). For the 26 BP-ALLs that lacked
p15
and/or p16 transcripts, only six (23%) exhibited low levels of
DHFR
by flow cytometry assay with Pt430, a fluorescent anti-folate. Conversely, 18 out of 37 (49%) BP-ALL samples with intact
p15
and/or p16 genes and transcripts showed low levels of
DHFR
(P = 0.04). In
p15
- and p16-null K562 cells transfected with a tetracycline-inducible
p15
cDNA construct, induction of
p15
transcripts and protein was accompanied by decreased growth rates, decreased S-phase fraction, decreased retinoblastoma protein phosphorylation, and markedly reduced levels of
DHFR
transcripts and protein. Collectively, our results suggest that losses of
p15
and/or p16 gene expression result in elevated levels of
DHFR
in BP-ALL in children. However, additional downstream factors undoubtedly also contribute to elevated levels of this enzyme target.
...
PMID:Relationship of p15 and p16 gene alterations to elevated dihydrofolate reductase in childhood acute lymphoblastic leukaemia. 1138 Apr 66
