Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA topoisomerase IIalpha (topo IIalpha) is an essential proliferation-dependent nuclear enzyme which has been exploited as an anti-tumor drug target. Since the proliferative status of human leukemia cells is associated with expression of the c-myb proto-oncogene, c-Myb was investigated as a trans-activator of the topo IIalpha gene. Using topo IIalpha promoter-luciferase reporter plasmids, c-myb expression caused trans-activation of the topo IIalpha promoter a maximum of approximately 4.5-fold over basal levels in HL-60 human promyelocytic leukemia cells. Trans-activation was submaximal with higher levels of c-myb expression plasmid but a Myb protein lacking its negative regulatory domain resulted in approximately 19-fold trans-activation. Mutagenesis and 5'-deletion studies revealed that Myb trans-activation was mediated via a Myb-binding site at positions -16 to -11 and that this region governed the bulk of basal topo IIalpha promoter activity in human leukemia cells. Trans-activation of topo IIalpha by c-Myb was lymphoid- or myeloid-dependent. However, B-Myb, a more widely-expressed Myb family member, caused topo IIalpha trans-activation in both HL-60 cells and HeLa epithelial cervical carcinoma cells. These data provide evidence for a new Myb-responsive gene which is directly linked to and required for cellular proliferation.
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PMID:c-Myb trans-activates the human DNA topoisomerase IIalpha gene promoter. 904 45

A defining feature of basal-like breast cancer, a breast cancer subtype with poor clinical prognosis, is the high expression of 'proliferation signature' genes. We identified B-Myb, a MYB family transcription factor that is often amplified and overexpressed in many tumor types, as being highly expressed in the proliferation signature. However, the roles of B-Myb in disease progression, and its mammary-specific transcriptional targets, are poorly understood. Here, we showed that B-Myb expression is a significant predictor of survival and pathological complete response to neoadjuvant chemotherapy in breast cancer patients. We also identified a significant association between the G/G genotype of a nonsynonymous B-Myb germline variant (rs2070235, S427G) and an increased risk of basal-like breast cancer [OR 2.0, 95% CI (1.1-3.8)]. In immortalized, human mammary epithelial cell lines, but not in basal-like tumor lines, cells ectopically expressing wild-type B-Myb or the S427G variant showed increased sensitivity to two DNA topoisomerase IIalpha inhibitors, but not to other chemotherapeutics. In addition, microarray analyses identified many G2/M genes as being induced in B-Myb overexpressing cells. These results confirm that B-Myb is involved in cell cycle control, and that its dysregulation may contribute to increased sensitivity to a specific class of chemotherapeutic agents. These data provide insight into the influence of B-Myb in human breast cancer, which is of potential clinical importance for determining disease risk and for guiding treatment.
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PMID:In vitro and in vivo analysis of B-Myb in basal-like breast cancer. 1904 54

The transcription factor MycN is the prototypical neuroblastoma oncogene and a potential therapeutic target. However, its strong expression caused by gene amplification in about 30% of neuroblastoma patients is a considerable obstacle to the development of therapeutic approaches aiming at eliminating its tumourigenic activity. We have previously reported that B-Myb is essentially required for transcription of the MYCN amplicon and have also shown that B-MYB and MYCN are engaged in a feed forward loop promoting the survival/proliferation of neuroblastoma cells. We postulated that pharmacological strategies breaking the B-MYB/MYCN axis should result in clinically desirable effects. Thus, we implemented a high throughput chemical screen, using a curated library of ~1500 compounds from the National Cancer Institute, whose endpoint was the identification of small molecules that inhibited B-Myb. At the end of the screening, we found that the compounds pinafide, ellipticine and camptothecin inhibited B-Myb transcriptional activity in luciferase assays. One of the compounds, the topoisomerase-1 inhibitor camptothecin, is of considerable clinical interest since its derivatives topotecan and irinotecan are currently used as first and second line treatment agents for various types of cancer, including neuroblastoma. We found that neuroblastoma cells with amplification of MYCN are more sensitive than MYCN negative cells to camptothecin and topotecan killing. Campothecin and topotecan caused selective down-regulation of B-Myb and MycN expression in neuroblastoma cells. Notably, forced overexpression of B-Myb could antagonize the killing effect of topotecan and camptothecin, demonstrating that the transcription factor is a key target of the drugs. These results suggest that camptothecin and its analogues should be more effective in patients whose tumours feature amplification of MYCN and/or overexpression of B-MYB.
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PMID:A chemical screen identifies the chemotherapeutic drug topotecan as a specific inhibitor of the B-MYB/MYCN axis in neuroblastoma. 2261 21