Journal Article

Regulation of the <i>Mdr1</i> isoforms in a <i>p53</i>-deficient mouse model

Jason A. Bush and Gang Li

in Carcinogenesis

Volume 23, issue 10, pages 1603-1607
Published in print October 2002 | ISSN: 0143-3334
Published online October 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.10.1603
Regulation of the Mdr1 isoforms in a p53-deficient mouse model

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Both p53 and multidrug transporters play important roles in chemoresistance. A transcriptional dependence of the Mdr1 gene promoter by p53 was first established a decade ago, and despite intense study, the p53-Mdr1 relationship still remains vague in vivo. The general model proposes that wild-type p53 down regulates, while mutant p53 up regulates, the Mdr1 promoter. Given that many studies have utilized cancer cell lines, minimal promoters and non-specific cDNA expression for in vitro experiments, we first sought to confirm the model using dermal fibroblasts isolated from the p53-knockout mice. We show that the gene products of the mouse Mdr1 homologue (Mdr1a and Mdr1b), namely P-glycoprotein (P-gp), appear upregulated at both the protein and mRNA levels in p53−/− mFbs compared with p53+/+ cells. We demonstrate that transient transfection of a mouse p53WT expression plasmid into short-term primary p53−/− fibroblasts can revert P-gp overexpression. The difference in P-gp levels has functional significance in that p53−/− fibroblasts are more resistant to doxorubicin and vincristine treatment and this resistance can be attenuated in the presence of the P-gp inhibitor, verapamil. Furthermore, we demonstrate that in kidney, spleen and testis, P-gp expression is elevated in the absence of p53. In contrast, other organs such as heart, liver, lung, brain, thymus and skeletal muscle, show no difference in expression between p53+/+ and p53−/− mice. Thus, our data shows a tissue-specific regulation of P-gp isoforms by p53 in the context of a p53-null mouse model.

Keywords: DOX, doxorubicin; P-gp, P-glycoprotein; Vin, vincristine

Journal Article.  3472 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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