In our previous funding period we established that expression of the hepatic multidrug resistance (MDR1) gene product, P-glycoprotein, varies over 50-fold among individuals. In addition, it was found that some individuals have the capability of inducing hepatic MDR1 in response to aromatic hydrocarbons while others do not. Differences in MDR1 regulatory sequences did not account for variability in MDR1 expression and the basis for lack of induction by xenobiotics in livers of some individuals is unknown. The studies supported by the continuation of this grant will show (based upon our preliminary studies) for the first time, that the tumor suppressor gene, p53, regulates expression of the endogenous MDR1 gene and that the transcription factor Egr-1 regulates MDR1 transcription. In addition, it is proposed that induction of MDR1 by the organochlorine pesticide, kepone, and the antihypertensive agent, reserpine, involves changes in the amounts or affinities of p53 and Egr- 1 for the MDR1 promoter. From these studies we propose four specific aims that will test the following hypotheses in rodent and human liver derived cells: (1) p53 plays a critical role in regulating human and rodent MDR1 genes. (2) The organochlorine pesticide, kepone may alter the expression, DNA binding activity or subcellular localization of p53 leading to profound effects on mdr1b expression. (3) The transcription factor Egr-1 is an important regulator of human and rodent MDR1 expression. (4) Reserpine may alter the expression or DNA-binding activity of Egr-1 leading to an up-regulation of mdr1b gene expression. These are the first studies to determine whether p53 regulates endogenous MDR1 and to elucidate the basis for p53 regulation of MDR1. Our work will allow us, based upon current and developing knowledge of p53 regulation, to identify new pathways affecting MDR1 gene expression. While this information should be broadly applicable to understanding variation in MDR1 gene expression, these findings should provide new insights into the evolution of multidrug resistance in tumors, especially those that have p53 alterations.
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