Nuclear factor-Y binding to the topoisomerase IIalpha promoter is inhibited by both the p53 tumor suppressor and anticancer drugs.
Expression of the human DNA topoisomerase IIalpha (topo IIalpha) gene is positively regulated by the binding of the nuclear factor Y (NF-Y) transcription factor to four of five inverted CCAAT boxes (ICBs) located in its promoter. We have demonstrated previously that expression of the p53 tumor suppressor inhibits human topo IIalpha promoter activity in murine (10)1 cells. In this report, we demonstrate that the inhibition of topo IIalpha gene expression by wild-type p53 correlates with the decreased binding of the transcription factor NF-Y to the first four ICBs of the topo IIalpha promoter. The expression of mutant p53 does not affect the binding of NF-Y. In NIH3T3 cells, we show that topo II-targeted drugs inhibit the binding of NF-Y to ICB sites in the topo IIalpha promoter. This effect is seen not only with drugs that result in DNA strand breaks but also with drugs that inhibit the catalytic activity of topo II, and even with the mitotic spindle inhibitor, vinblastine. Further experiments with p53-null (10)1 cells treated with these same drugs also demonstrate decreased NF-Y binding to the topo IIalpha ICBs. The data presented points to the existence of both p53-dependent and -independent mechanisms for regulating NF-Y binding to ICBs in the topo IIalpha promoter and thus the modulation of topo IIalpha gene expression.
Joshi
Ashish A
AA
Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Wu
Zhong
Z
Reed
Robin F
RF
Suttle
D Parker
DP
D016475:3T3 Cells; D000818:Animals; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D023081:CCAAT-Binding Factor / Q000187:drug effects / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins; D015870:Gene Expression / Q000187:drug effects*; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D023081:CCAAT-Binding Factor; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C402244:nuclear factor Y; D004250:DNA Topoisomerases, Type II