TY - JOUR
T1 - Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743
AU - Minuzzo, Mario
AU - Marchini, Sergio
AU - Broggini, Massimo
AU - Faircloth, Glynn
AU - D'Incalci, Maurizio
AU - Mantovani, Roberto
PY - 2000/6/6
Y1 - 2000/6/6
N2 - Ecteinascidin-743 (ET-743) is a tetrahydroisoquinoline alkaloid isolated from the tunicate Ecteinascidia turbinata currently under phase II clinical trials for its potent anticancer activity. ET-743 binds DNA in the minor groove and forms covalent adducts with some sequence specificity. It selectively inhibits in vitro binding of the CCAAT box factor NF-Y. In this study, we assayed ET-743 function in vivo on the HSP70 promoter. On heat induction, the drug blocks transcription rapidly at pharmacological concentrations and in a CCAAT-dependent manner, whereas the activity of the CCAAT-less simian virus 40 promoter is not affected. The effect is exerted at the mRNA level. The distamycin-like alkylating tallimustine is inactive in these assays. Binding of NF-Y and of the heat-shock factor is normal in ET- 743-treated cells. Run-on analysis of several endogenous genes further proves that the drug has rapid, profound, and selective negative effects on transcription. Thus, this marine-derived compound is a promoter-specific, transcription-interfering agent.
AB - Ecteinascidin-743 (ET-743) is a tetrahydroisoquinoline alkaloid isolated from the tunicate Ecteinascidia turbinata currently under phase II clinical trials for its potent anticancer activity. ET-743 binds DNA in the minor groove and forms covalent adducts with some sequence specificity. It selectively inhibits in vitro binding of the CCAAT box factor NF-Y. In this study, we assayed ET-743 function in vivo on the HSP70 promoter. On heat induction, the drug blocks transcription rapidly at pharmacological concentrations and in a CCAAT-dependent manner, whereas the activity of the CCAAT-less simian virus 40 promoter is not affected. The effect is exerted at the mRNA level. The distamycin-like alkylating tallimustine is inactive in these assays. Binding of NF-Y and of the heat-shock factor is normal in ET- 743-treated cells. Run-on analysis of several endogenous genes further proves that the drug has rapid, profound, and selective negative effects on transcription. Thus, this marine-derived compound is a promoter-specific, transcription-interfering agent.
KW - DNA binding
KW - Drug
KW - Transcription
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U2 - 10.1073/pnas.97.12.6780
DO - 10.1073/pnas.97.12.6780
M3 - Article
C2 - 10841573
AN - SCOPUS:0034612344
VL - 97
SP - 6780
EP - 6784
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 12
ER -