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:5.99.1.2 (
topoisomerase
)
9,166
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Alterations in the amino acid composition, phosphorylation pattern, or intracellular levels of
topoisomerase
II have been associated with resistance to antineoplastic agents whose effects are mediated through interactions with this enzyme. To develop a model system with which to investigate the determinants of
topoisomerase
II sensitivity or resistance to antineoplastic agents that target this enzyme, a cDNA encoding the wild-type Drosophila melanogaster
topoisomerase
II was ligated into a mammalian expression vector containing a glucocorticoid-inducible mouse mammary tumor virus promoter and transfected into an epipodophyllotoxin-resistant Chinese hamster ovary cell line (
VPM
(r)-5). In two transfectants carrying an intact, full-length Drosophila
topoisomerase
II cDNA, exposure to the inducing agent, dexamethasone (10 microM), resulted in complementation of the endogenous mutant
topoisomerase
II and phenotypic reversion to etoposide sensitivity. In the presence of glucocorticoid, etoposide-induced cytotoxicity increased 20-fold, despite the fact that Drosophila
topoisomerase
II mRNA expression was only 0.1% of that of the endogenous mammalian
topoisomerase
II. Induced cells demonstrated a marked increase in DNA single strand breaks compared with uninduced resistant cells, thereby providing biochemical evidence supporting increased DNA strand cleavage due to activation of the Drosophila enzyme. These observations demonstrate the ability of a wild-type Drosophila
topoisomerase
II to complement a mutant mammalian enzyme and suggest that transfectants capable of conditional
topoisomerase
II expression represent a useful model for studies of the biochemical pharmacology and structure-function relationships of normal and mutant enzymes.
...
PMID:Conditional expression of wild-type topoisomerase II complements a mutant enzyme in mammalian cells. 839 Sep 79
