Down-regulation of human topoisomerase IIalpha correlates with altered expression of transcriptional regulators NF-YA and Sp1.
Topoisomerase IIalpha (Topo IIalpha) is an essential nuclear enzyme with a role in the maintenance of DNA topology. Topo IIalpha is a target for several anticancer drugs and the levels of activity of this enzyme have been implicated in the development of drug resistance. Our objective was to identify regulatory transcription factors involved in drug-induced down-regulation of Topo IIalpha. A breast cancer cell line was subjected to a pulsed exposure of doxorubicin and resistant clones propagated. Whole-cell extracts were studied by immunoblotting and RT-PCR for drug-induced changes in the amounts Topo IIalpha, Sp1, Sp3, NF-Y and MDR1. Topo IIalpha levels were reduced in six out of eight cell lines. Of these, three showed concomitant changes in the expression of Sp1 and NF-YA. Thus, we provide the first evidence for roles of Sp1 and NF-Y in bringing about the drug-induced down-regulation of Topo IIalpha gene expression.
Allen
Kirsty A
KA
Institute of Molecular BioSciences, Massey University, Palmerston North, New Zealand.
Williams
Amram O
AO
Isaacs
Richard J
RJ
Stowell
Kathryn M
KM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000951:Antigens, Neoplasm; D023081:CCAAT-Binding Factor / Q000096:biosynthesis* / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D002457:Cell Extracts; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D016329:Sp1 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; D023081:CCAAT-Binding Factor; D002457:Cell Extracts; D004268:DNA-Binding Proteins; C492061:NFYA protein, human; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II