The expression of P-glycoprotein in tissues from wild-type p53 and transgenic p53 knockout mice

The overexpression of P-glycoprotein (P-gp) in response to chemotherapy in multi-drug resistant tumor cells is well documented but the mechanisms regulating P-gp expression in normal and tumor tissues remains unclear. The tumor suppressor gene p53 has been implicated in the transcriptional regulation of mdr. In this study we examined the P-gp expression in p53 wild type mice and transgenic p53 knockout (KO) mice to study the physiologic relationship of p53 and P-gp. The level of P-gp by Western analysis and of mdr1a RNA by Northern was measured in adrenal gland, brain, colon, heart, kidney, liver, lung, skin, spleen, and testis from five p53 and five p53 KO male adult mice. We found P-gp expression in all tissues but there was individual variation among animals. Overall, tissues from the lung, spleen and testis consistently showed higher P-gp expression in p53 KO mice than in wild type, whereas spleen cells expressed lower levels of P-gp. Northern analysis showed significantly higher mdr1a expression in liver tissues from p53 KO than from wild type mice. Our results suggest that the regulation of P-gp expression by p53 may be different from tissue to tissue and suggest that other effectors may modulate the p53 regulation of P-gp expression.

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