Response of p53 promoter to hydrogen peroxide

Momand, Jamil

Abstract

Cancer cells often contain corrupted p53 response pathways. Artificial activation of the p53 response pathway or re-introduction of the normal p53 has been shown to promote apoptosis in cancer cells. In approximately 75% of breast cancers the p53 gene is wild type but, in many cases, is transcribed at a lower than normal rate. If one could identify mechanisms that increase the p53 transcription rate it may be possible to develop therapies that destroy cancer cells. It is our goal to elucidate the molecular mechanisms that regulate p53 transcriptional activity with the hope that the knowledge gained can be used to fight breast cancer. We found that hydrogen peroxide treatment of breast cancer cells increases the p53 mRNA and protein level indicating that a hydrogen peroxide-responsive element likely lies within the p53 promoter. Inhibition studies show that free radicals appear to be required for p53 mRNA level induction. Analysis of the p53 promoter indicates that it contains binding sites for AP-1 and NF-kB--two transcription factors previously shown to be activated upon hydrogen peroxide treatment of cells. We hypothesize that hydrogen peroxide activates AP-1 and NF-kB to bind the p53 promoter and increase transcription of the p53 gene. To test this hypothesis we will answer the following questions: 1) Does the p53 promoter contain a hydrogen peroxide responsive element? 2) Does hydrogen peroxide activate AP-1 and NF-kB to bind the p53 promoter? The response of the p53 gene to reactive oxygen species generating molecules represents an important gap in our knowledge. If the responsive element within the p53 promoter can be identified we may be able to develop agents that reactivate p53 in breast cancers. This study will contribute to our understanding of the p53 signaling pathways and to a possible treatment for breast cancer patients.