ELUCIDATING THE FUNCTION OF P53-MEDIATED IL17RB REPRESSION

ABSTRACT In addition to its pivotal roles in regulating cell cycle arrest, apoptosis, DNA repair, and metabolism, the p53 tumor suppressor has been demonstrated to modulate innate immune and adaptive immune responses through its crosstalk with key regulators of immune signaling pathways. The dysregulation of Interleukin 17 (IL17)

cytokine family and its receptors has been associated with many human diseases, notably inflammation and cancer, crediting to their crucial roles in normal host immune responses. Particularly, Interleukin 17 Receptor B (IL17RB) has been found to be overexpressed in various cancers through the activation of NFB, AKT, or ERK

signaling to promote tumorigenesis. Our preliminary results indicate that IL17RB is a p53 repression target and repression of IL17RB sustains the p53 response. Additionally, activation of p53 by nutlin-3a or IL17RB depletion decreases the expression of pro-inflammatory cytokine IL8 induced by lipopolysaccharide (LPS). The goal of

this application is to study the role of p53-mediated IL17RB repression in tumor suppression and inflammation inhibition. We established systems of IL17RB repression, overexpression, and activation, that will enable biochemical and cellular characterization as well as in-depth gene expression analyses to elucidate the

contribution of IL17RB repression to tumor suppressive and inflammation inhibitory function of p53. The proposed work will not only allow us to gain a better understanding on how IL17RB links p53’s crosstalk with other signaling pathways and how p53 attenuates oncogenic effects of chronic inflammation through repressing

IL17RB, but also provide a mechanistic basis for the development of novel anti-cancer strategies as well as inflammation inhibitors. In addition, this project will enhance the research environment at St. John’s University by providing undergraduate and graduate students with numerous opportunities to learn the fundamentals of

biomedical research.