Wild-type p53 marginally induces endogenous MDR-1 mRNA without causing a measurable drug resistance in human cancer cells

The notion that wt p53 downregulates MDR-1 links p53 mutations to multidrug resistant phenotype. Alternatively, it has been envisioned that wt p53 pro tects cells against DNA damaging drugs by inducing MDR-1. Opposing conclusi ons on the relationship between MDR-1 and p53 have been predominantly based on the effects of p53 on MDR-1 promoter-constructs. We found that introduc tion of wt p53 slightly induced MDR-1 mRNA in three cell lines having endog enous mt p53. Wt p53-mediated induction of endogenous MDR-1 may represent a rudiment of cellular protection against toxic compounds earlier in evoluti on. Marked induction of p21(WAF1/CIP1) (p21) mRNA was observed in all cell lines; and lower levels of wt p53 were required to induce p21 than MDR-1. P gp was undetectable and wt p53 did not increase resistance to an MDR-1 subs trate, suggesting the changes in MDR-1 mRNA may be functionally insignifica nt. Unlike endogenous MDR-1, the expression of an MDR-1 promoter (-434/+147 fragment) - luciferase construct was unchanged or even inhibited by wt p53 that may be secondary to wt p53-mediated cytotoxicity. Thus, partial promo ter constructs may not accurately represent endogenous MDR-1.