Photo of Sam Lee,  PhD

Sam Lee, PhD

Massachusetts General Hospital

Massachusetts General Hospital
Phone: (617) 726-6691


swlee@mgh.harvard.edu

Sam Lee, PhD

Massachusetts General Hospital

EDUCATIONAL TITLES

  • Associate Professor, Dermatology, Harvard Medical School
  • Associate Director of CBRC, Dermatology, Massachusetts General Hospital

DF/HCC PROGRAM AFFILIATION

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.

Publications

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  • Muñoz-Fontela C, Mandinova A, Aaronson SA, Lee SW. Emerging roles of p53 and other tumour-suppressor genes in immune regulation. Nat Rev Immunol 2016. PubMed
  • Ongusaha PP, Kim HG, Boswell SA, Ridley AJ, Der CJ, Dotto GP, Kim YB, Aaronson SA, Lee SW. RhoE Is a Pro-Survival p53 Target Gene that Inhibits ROCK I-Mediated Apoptosis in Response to Genotoxic Stress. Curr Biol 2016; 26:2221-2222. PubMed
  • Hwang SY, Deng X, Byun S, Lee C, Lee SJ, Suh H, Zhang J, Kang Q, Zhang T, Westover KD, Mandinova A, Lee SW. Direct Targeting of β-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt/β-Catenin Signaling. Cell Rep 2016; 16:28-36. PubMed
  • Neel VA, Todorova K, Wang J, Kwon E, Kang M, Liu Q, Gray N, Lee SW, Mandinova A. Sustained Akt Activity Is Required to Maintain Cell Viability in Seborrheic Keratosis, a Benign Epithelial Tumor. J Invest Dermatol 2016; 136:696-705. PubMed
  • Byun S, Shin SH, Park J, Lim S, Lee E, Lee C, Sung D, Farrand L, Lee SR, Kim KH, Dong Z, Lee SW, Lee KW. Sulforaphene suppresses growth of colon cancer-derived tumors via induction of glutathione depletion and microtubule depolymerization. Mol Nutr Food Res 2016. PubMed
  • Byun S, Lim S, Mun JY, Kim KH, Ramadhar TR, Farrand L, Shin SH, Thimmegowda NR, Lee HJ, Frank DA, Clardy J, Lee SW, Lee KW. Identification of a Dual Inhibitor of Janus Kinase 2 (JAK2) and p70 Ribosomal S6 Kinase1 (S6K1) Pathways. J Biol Chem 2015; 290:23553-62. PubMed
  • Hiraki M, Hwang SY, Cao S, Ramadhar TR, Byun S, Yoon KW, Lee JH, Chu K, Gurkar AU, Kolev V, Zhang J, Namba T, Murphy ME, Newman DJ, Mandinova A, Clardy J, Lee SW. Small-Molecule Reactivation of Mutant p53 to Wild-Type-like p53 through the p53-Hsp40 Regulatory Axis. Chem Biol 2015; 22:1206-16. PubMed
  • Namba T, Chu K, Kodama R, Byun S, Yoon KW, Hiraki M, Mandinova A, Lee SW. Loss of p53 enhances the function of the endoplasmic reticulum through activation of the IRE1α/XBP1 pathway. 2015; 6:19990-20001. PubMed
  • Yoon KW, Byun S, Kwon E, Hwang SY, Chu K, Hiraki M, Jo SH, Weins A, Hakroush S, Cebulla A, Sykes DB, Greka A, Mundel P, Fisher DE, Mandinova A, Lee SW. Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53. Science 2015; 349:1261669. PubMed
  • Yoon, K.W., Byun, S., Hwang, S.-Y., Kwon, E., Chu, K., Hiraki, M., Weins, A., Hakroush, S., Cebulla, A., Greka, A., Mundel, P., Sykes, D.B., Fisher, D.E., Mandinova, A. & Lee, S.W.. Control of signalingmediated clearance of apoptotic cells by the tumor suppressor p53. Science 2015.