期刊
MOLECULAR CANCER THERAPEUTICS
卷 7, 期 5, 页码 1319-1328出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-07-0475
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资金
- MRC [G0000168] Funding Source: UKRI
- Medical Research Council [G0000168] Funding Source: researchfish
- Cancer Research UK [C2559/A3083] Funding Source: Medline
- Medical Research Council [G0000168] Funding Source: Medline
Many genes involved in cell cycle control have promoters that bind the heterotrimeric transcription factor NF-Y. Several minor-groove binding drugs have been shown to block interactions of transcription factors with cognate DNA-binding sequences. We showed previously that noncovalent minor-groove binding agents block interactions of NF-Y with the promoter of topoisomerase II alpha (topo II alpha). In this study, we investigated the ability of GWL-78, a pyrrolobenzodiazepine-poly(N-methylpyrrole) conjugate, to inhibit the binding of NF-Y to DNA. Electrophoretic mobility shift assays showed that GWL-78 could displace NF-Y bound to several CCAAT motifs within promoters of genes involved in cell cycle progression. DNase I footprinting of the topo II alpha promoter confirmed binding of GWL-78 to AT-rich sequences corresponding to the preferred binding site of NF-Y. Incubation with GWL-78 resulted in displacement of NF-Y binding to DNA. Chromatin immunoprecipitation assays on the topo II alpha promoter showed that GWL-78 was able to enter the nucleus and interact with specific DNA sequences. Treatment of NIH3T3 cells with GWL-78 resulted in a block of cell cycle progression, which did not involve activation of p53. Thus, agents such as GWL-78 may be useful in modulating transcription and blocking cellular proliferation.
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