Research Abstract

My laboratory studies how tumor suppressor p53-mediated transcriptional regulation influences cell fate decisions: live or die. Genotoxic stress, including radiation and chemo agents, ultimately eliminate tumor cells by the induction of apoptosis. p53 is indispensable for maintenance of genomic integrity. p53 functions as a transcription factor that is activated by various cellular stresses and governs multiple core programs in cells, including cell cycle arrest and apoptosis. Over the past decades, enormous efforts have been made toward understanding various mechanisms of p53-mediated cell death/apoptosis. However, the involvement of p53 in post-apoptosis has yet to be addressed. In this application, we found that p53, a master regulator of apoptosis, controls phagocytosis-mediated clearance of dead cells via its new target DD1α. We demonstrate that p53→DD1α plays an indispensable role in “eat-me” signalingmediated

phagocytosis, suggesting that p53 promotes not only the pro-/pre-apoptotic pathway but also post-apoptotic events. It has been strongly suggested that prompt and efficient clearance of apoptotic cells is the ultimate goal of the apoptotic program, as well as a key process that can prevent inflammation to maintain tolerance under physiological conditions. We discovered that DD1α functions as an engulfment ligand or receptor that involves in homophilic intermolecular interaction at intercellular junctions of apoptotic cells and macrophages in vitro and in vivo. We also found that loss of DD1α impairs the engulfment of apoptotic cells following apoptotic stress such as ionizing radiation, leading to accumulation of dying cells within tissues and the development of a severe autoimmune phenotype in vivo. Moreover, DD1α appears to function as a negative immune-checkpoint regulator that is critical in modulating immune response/T cell function, suggesting the role of DD1α in immune surveillance. Thus, p53-induced expression of DD1α is a vital phase for the phagocytic engulfment process of dead cells, and then facilitates the step-wise priming of immune surveillance. Based on these novel findings, we focus on mechanisms of understanding the roles of a newly found first post-apoptotic target of p53 via ‘eat-me signaling’ and investigating the therapeutic potential to enhance the anti-tumor immune responses.