Cancer chemoresistance: the relationship between p53 and multidrug transporters.
Extensive studies indicate that both p53 and multidrug transporters play important roles in chemoresistance. Since the initial reports a decade ago demonstrating a transcriptional dependence of the ABCB1 gene (MDR) promoter by p53, much data have been accumulated. However, despite being the subject of intense study, this p53-MDR relationship remains unclear in human cancers. The data are confounded by variable and contrasting results when considering the in vitro regulation and attempting to draw parallels in tissue specimens. The original model suggested that wild-type p53 downregulates the ABCB1 promoter, whereas mutant p53 increases expression of ABCB1. This review summarizes the data for and against this hypothesis. What emerges from these studies is a complex picture, where data have been obtained in support of this hypothesis, but there are also many circumstances where it is not supported. Taken together, these data suggest that the relationship between p53 and multidrug transporters is conditional. It is dependent on cellular environment, the drug used, and the nature of the p53 mutation.
Bush
Jason A
JA
Division of Dermatology, Department of Medicine, Vancouver Hospital and Health Sciences Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Li
Gang
G
D017209:Apoptosis / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D016158:Genes, p53 / Q000502:physiology*; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D009369:Neoplasms / Q000378:metabolism*
D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1