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 protects cells against DNA damaging drugs by inducing MDR-1. Opposing conclusions 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 introduction of wt p53 slightly induced MDR-1 mRNA in three cell lines having endogenous mt p53. Wt p53-mediated induction of endogenous MDR-1 may represent a rudiment of cellular protection against toxic compounds earlier in evolution. Marked induction of p21WAF1/CIP1 (p21) mRNA was observed in all cell lines; and lower levels of wt p53 were required to induce p21 than MDR-1. Pgp was undetectable and wt p53 did not increase resistance to an MDR-1 substrate, suggesting the changes in MDR-1 mRNA may be functionally insignificant. 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 promoter constructs may not accurately represent endogenous MDR-1.
Nicoletti
M I
MI
Medicine Branch and Developmental Therapeutics Program, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Myers
T G
TG
Fojo
T
T
Blagosklonny
M V
MV
D000256:Adenoviridae; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D019450:Genes, MDR / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D007763:Lac Operon; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000494:pharmacology*; D020741:rho GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D003609:Dactinomycin; D020741:rho GTP-Binding Proteins