p53 regulates the minimal promoter of the human topoisomerase IIalpha gene.
DNA topoisomerase IIalpha is an essential enzyme for chromosome segregation during mitosis. Consistent with a cell division-specific role, the expression of the topoisomerase IIalpha gene is strongly influenced by the proliferation status of cells. The p53 protein is one of the most important regulators of cell cycle progression in mammals, with an apparent dual role in the induction of cell cycle arrest following cytotoxic insults and in the regulation of the apoptotic cell death pathway. We have analysed whether p53 plays a role in regulating expression of the human topoisomerase IIalpha gene. We show that wild-type, but not mutant, p53 is able to decrease substantially the activity of the full length topoisomerase IIalpha gene promoter. Using a series of constructs comprising various deleted or mutated versions of the promoter lacking critical cis-acting elements, we show that this p53-specific regulation of the topoisomerase IIalpha promoter is independent of all characterised transcription factor binding sites and is directed at the minimal gene promoter. We conclude that expression of wild-type p53 induces downregulation of the human topoisomerase IIalpha promoter by acting on the basal transcription machinery. These findings implicate topoisomerase II as one of the downstream targets for p53-dependent regulation of cell cycle progression in human cells.
Sandri
M I
MI
Imperial Cancer Research Fund, University of Oxford, John Radcliffe Hospital, UK.
Isaacs
R J
RJ
Ongkeko
W M
WM
Harris
A L
AL
Hickson
I D
ID
Broggini
M
M
Vikhanskaya
F
F
D000951:Antigens, Neoplasm / Q000235:genetics*; D002460:Cell Line; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D010051:Ovarian Neoplasms; D011401:Promoter Regions, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D016159:Tumor Suppressor Protein p53; D004250:DNA Topoisomerases, Type II