p53 regulates the minimal promoter of the human topoisomerase Ha gene

摘要

DNA topoisomerase IIα is an essential enzyme for chromosome segregation during mitosis. Consistent with a cell division-specific role, the expression of the topoisomerase IIα gene is strongly influenced by the proliferation status of cells. The p53protein 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 analysedwhether p53 plays a role in regulating expression of the human topoisomerase Ilα gene. We show that wild-type, but not mutant, p53 is able to decrease substantially the activity of the full length topoisomerase Ila 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 Ilα 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 Ilα promoter by acting on the basal transcription machinery. These findings implicate topoisomerase II as oneof the downstream targets for p53-dependent regulation of cell cycle progression in human cells.