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

  • Authors:
    • Maria Ines Nicoletti
    • Timothy G. Myers
    • Tito Fojo
    • Mikhail V. Blagosklonny
  • View Affiliations

  • Published online on: February 1, 2001     https://doi.org/10.3892/ijo.18.2.375
  • Pages: 375-381
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Abstract

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.

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February 2001
Volume 18 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Nicoletti MI, Myers TG, Fojo T and Blagosklonny MV: Wild-type p53 marginally induces endogenous MDR-1 mRNA without causing a measurable drug resistance in human cancer cells. Int J Oncol 18: 375-381, 2001
APA
Nicoletti, M.I., Myers, T.G., Fojo, T., & Blagosklonny, M.V. (2001). Wild-type p53 marginally induces endogenous MDR-1 mRNA without causing a measurable drug resistance in human cancer cells. International Journal of Oncology, 18, 375-381. https://doi.org/10.3892/ijo.18.2.375
MLA
Nicoletti, M. I., Myers, T. G., Fojo, T., Blagosklonny, M. V."Wild-type p53 marginally induces endogenous MDR-1 mRNA without causing a measurable drug resistance in human cancer cells". International Journal of Oncology 18.2 (2001): 375-381.
Chicago
Nicoletti, M. I., Myers, T. G., Fojo, T., Blagosklonny, M. V."Wild-type p53 marginally induces endogenous MDR-1 mRNA without causing a measurable drug resistance in human cancer cells". International Journal of Oncology 18, no. 2 (2001): 375-381. https://doi.org/10.3892/ijo.18.2.375