BMC Seminar Friday, May 18 at 12:00 in room 343 Læknagarður

Speaker: Dr. Barbara Hopkins, postoctoral research associate, University of Pittsburgh School of Medicine Women's Cancer Research Center.

Title: A PRDX1-FOXO3 SIGNALING PATHWAY ACTS AS A REDOX SENSOR CONTROLLING FOXO3 SUBCELLULAR LOCALIZATION AND TARGET GENE TRANSACTIVATION

Abstract:

Precision in redox signaling is attained through posttranslational protein modifications such as oxidation of protein thiols. The peroxidase peroxiredoxin 1 (PRDX1) regulates signal transduction through changes in thiol oxidation of its cysteines. Our research demonstrates that PRDX1 is a binding partner for the tumor suppressive transcription factor FOXO3 that directly regulates the FOXO3 stress response. Heightened oxidative stress evokes formation of disulfide bound heterotrimers linking dimeric PRDX1 to monomeric FOXO3. Absence of PRDX1 enhances FOXO3 nuclear localization and transcription that are dependent on the presence of Cys31 or Cys150 within FOXO3. Notably, FOXO3-T32 phosphorylation is constitutively enhanced in these mutants, but nuclear translocation of mutant FOXO3 is restored with PI3K inhibition. We show that on H₂O₂ exposure, transcription of tumor suppressive miRNAs let7b and let-7c is regulated by FOXO3 or PRDX1 expression levels and that let-7c is a novel target for FOXO3. Conjointly, inhibition of let-7 microRNAs increases let-7-phenotypes in PRDX1-deficient breast cancer cells. Altogether, these data ascertain the existence of an H₂O₂- sensitive PRDX1-FOXO3 signaling axis that fine tunes FOXO3 activity toward the transcription of gene targets in response to oxidative stress. The public health significance of this research lies in the fact that elevated levels of oxidative stress in a major cancer risk factor. In breast cancer it has been found that post-menopausal women, who are generally at increased risk for breast cancer development, show an even higher level of oxidative stress markers. Unfortunately, antioxidant therapies have proven ineffectual. If we can gain a deeper understand of how these oxidative stress induced redox signaling pathways work, it is possible to develop more effective therapies for those at-risk patients for whom therapies fail.