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)
Ochratoxin A
(
OTA
) is a potent renal carcinogen, but little is known regarding the mechanism of
OTA
carcinogenicity. Early histopathological alterations induced by
OTA
in rat kidney include single cell death, stimulation of cell proliferation and prominent karyomegaly indicative of blocked nuclear division during mitosis. Based on these observations, it has been suggested that disruption of mitosis by
OTA
may be the principal cause of cell death and subsequent trigger for cell proliferation to compensate for cell loss. To gain further insight into the molecular mechanism of
OTA
toxicity, we used targeted quantitative real-time polymerase chain reaction arrays to investigate the expression of genes involved in cell cycle control and mitosis in kidneys of male F344 rats treated with 0, 21, 70 and 210 microg/kg body wt
OTA
for up to 90 days. Treatment with
OTA
resulted in overexpression of key regulators of mitosis, including the mitotic protein kinases Polo-like kinase 1, Aurora B and cyclin-dependent kinase 1 (Cdk1Cdc2), several cyclins and cyclin-dependent kinase inhibitors,
topoisomerase
II and survivin. Immunohistochemical analysis confirmed upregulation of Cdk1, p21(WAF1/CIP1),
topoisomerase
II and survivin in S3 proximal tubule cells, from which
OTA
-induced tumors in rats arise, and demonstrated increased phosphorylation of histone H3, a target of Aurora B. Importantly, many of the genes found to be deregulated in response to
OTA
have been linked to chromosomal instability and malignant transformation, supporting the hypothesis that aberrant mitosis, resulting in blocked or asymmetric cell division, accompanied by an increased risk of aneuploidy acquisition, may play a critical role in
OTA
carcinogenicity.
...
PMID:Modulation of key regulators of mitosis linked to chromosomal instability is an early event in ochratoxin A carcinogenicity. 1923 4
Ochratoxin A
(
OTA
), a known nephrotoxin and carcinogenic mycotoxin, was investigated to examine its effectiveness to induce cytotoxicity and DNA damage (Comet assay), as well as its possible inhibition of
topoisomerase
II (topo II) catalytic activity in cultured Chinese hamster ovary (CHO) cells. The analysis of
OTA
-induced DNA strand breaks as well as the flow cytometric assessment of polyploidy has provided evidence that is consistent with the idea of a mixed mode of action of the mycotoxin: in addition to its genotoxic activity,
OTA
may also interfere with chromosome distribution during cell division.
...
PMID:The mycotoxin ochratoxin A inhibits DNA topoisomerase II and induces polyploidy in cultured CHO cells. 1949 Sep 38
