Nucleic Acids Research, Vol 24, Issue 22 4464-4470, Copyright © 1996 by Oxford University Press
MI Sandri, RJ Isaacs, WM Ongkeko, AL Harris, ID Hickson, M Broggini and F Vikhanskaya
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.
ARTICLES
p53 regulates the minimal promoter of the human topoisomerase IIalpha gene
Imperial Cancer Research Fund, University of Oxford, John Radcliffe Hospital, UK.
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