Modulation of Activity of the Promoter of the Human <i>MDR</i> 1 Gene by Ras and p53

TLDR

Drug resistance in human cancer is driven by overexpression of the MDR1 gene, which can arise de novo and whose promoter is regulated by oncogenic Ras and tumor‑suppressor p53. The oncogene c‑Ha‑Ras stimulates MDR1 non‑specifically, while mutant p53 activates and wild‑type p53 represses the promoter, suggesting MDR1 activation during tumor progression linked to Ras and p53 mutations.

Abstract

Drug resistance in human cancer is associated with overexpression of the multidrug resistance (MDR1) gene, which confers cross-resistance to hydrophobic natural product cytotoxic drugs. Expression of the MDR1 gene can occur de novo in human cancers in the absence of drug treatment. The promoter of the human MDR1 gene was shown to be a target for the c-Ha-Ras-1 oncogene and the p53 tumor suppressor gene products, both of which are associated with tumor progression. The stimulatory effect of c-Ha-Ras-1 was not specific for the MDR1 promoter alone, whereas a mutant p53 specifically stimulated the MDR1 promoter and wild-type p53 exerted specific repression. These results imply that the MDR1 gene could be activated during tumor progression associated with mutations in Ras and p53.