Mutant p53 cooperates with ETS and selectively up-regulates human MDR1 notMRP1

The most frequently expressed drug resistance genes, MDR1 and MRP1, occur i n human tumors with mutant p53. However, it was unknown if mutant p53 trans criptionally regulated both MDR1 and MRP1. We demonstrated that mutant p53 did not activate either the MRP1 promoter or the endogenous gene. In contra st, mutant p53 strongly up-regulated the MDR1 promoter and expression of th e endogenous MDR1 gene. Notably, cells that expressed either a transcriptio nally inactive mutant p53 or the empty vector showed no endogenous MDR1 up- regulation. Transcriptional activation of the MDR1 promoter by mutant p53 r equired an Ets binding site, and mutant p53 and Ets-1 synergistically activ ated MDR1 transcription. Biochemical analysis revealed that Ets-1 interacte d exclusively with mutant p53s in vivo but not with wild-type p53. These fi ndings are the first to demonstrate the induction of endogenous MDR1 by mut ant p53 and provide insight into the mechanism.