Massachusetts General Hospital
Cutaneous Biology Research Center
Building 149, 13th Street
Charlestown, MA 02129
Since my years as a Harvard faculty member, I have focused a sustained effort toward cancer biology, and my initial most significant contribution was the first to discover that pro-survival pathway activation is directly associated with p53-dependent genotoxic responses in cancer cells, and have provided a unique and significant contribution in this area. As an Assistant and then as an Associate Professor at the BIDMC and the MGH/Harvard Medical School, I pursued my major interest in how tumor suppressor p53-mediated transcriptional regulation influences cell fate decisions: live or die. Based on my contribution concerning the dark side of p53 in cancer therapeutics that wt-p53 can function as a guardian of cancer genome for their survival against therapeutic stress, I have established close collaborations with the Broad Institute utilizing their technological, computational and chemical biological tools under their Chemical Genetics Platform. Together with Broad scientists, I have identified several promising small molecules with anti-cancer activity through the activation of tumor suppressor p53 apoptotic pathway. Specifically, we have identified a small molecule to induce apoptosis selectively in cells having a cancer genotype by targeting a non-oncogene co-dependency acquired by the expression of the cancer genotype in response to transformation-induced oxidative stress. This highlights a novel strategy for cancer therapy that preferentially eradicates cancer cells by targeting the ROS stress-response pathway. My experience in this area has played a major role in the development of a Chemical Genetics Core facility at CBRC in collaboration with the Broad Institute. My group now possesses considerable experience in systematic small molecule technologies. I will continue to assist with the design, validation, execution and interpretation of investigator initiated chemical genetic screens.
Aditi U Gurkar
So Young Hwang
Hyung Gu Kim
Kyoung Wan Yoon
Han, J.A., Kim, J.-I., Hwang, D.H., Ballou, L.R., Mahale, A., Aaronson, A.A., and Lee, S.W. p53-mediated induction of Cox-2 counteracts p53- or genotoxic stress-mediated apoptosis. EMBO J. 21: 5635-5644, 2002.
Macip, S., Igarashi, M., Fang, L., Lee, S.W., and Aaronson, S.A. Inhibition of p21Waf1/Cip1/Sdi1-mediated ROS accumulation can rescue p21-induced senescence. EMBO J. 21: 2180- 2188, 2002.
Wulf, G.M., Loiu, Y.-C., Ryo, A., Lee, S.W., and Lu, K.P. Role of Pin1 in regulation of p53 stability and p21 transactivation, and cell cycle checkpoints in response to DNA damage. J. Biol. Chem. 277: 47976-47979, 2002.
Ryo, A., Wulf, G.M., Loiu, Y.-C., Lee, S.W., and Lu, K.P. Pin1 is an E2F target gene essential for Neu/Ras-induced transformation of mammary epithelial cells. Mol. Cell. Biol. 22:5281-5295, 2002.
Ohtsuka, T., Ryu, H., Minamishima, Y.A., Ryo, A., and Lee, S.W. Modulation of p53 and p73 levels by cyclin G: implication of a negative feedback regulation. Oncogene, 22: 1678-1687, 2003.
Ongusaha, P.P., Ouchi, T., Kim, K.T., Nytko, E., Kwak, J.C., Deng, C.-X., and Lee, S.W. BRCA1 shifts p53-mediated cellular outcomes toward irreversible growth arrest. Oncogene, 22: 3749-3758, 2003.
Ongusaha, P., Kim, J-I., Fang, L. Wong, T.W., Yancopoulos, G.D., Aaronson, A.A., and Lee, S.W. p53 induction and activation of DDR1 kinase counteract p53-mediate apoptosis and influence p53 regulation through a positive feedback loop. EMBO J. 22: 1289-1301, 2003.
Aglipay, J.A., Lee, S.W., Okada, S., Kwak, J.C., Qin, J., and Ouchi, T. A Member of the PYRIN Family, IFI16, is a Novel BRCA1-associated Protein Involved in the p53-mediated Apoptosis Pathway. Oncogene 22: 8931-8938, 2003.
Kwak, J.C., Ongusaha, P.P., Ouchi, T., and Lee, S.W. IFI16 as a negative regulator in the regulation of p53 and p21Waf1. J. Biol. Chem. 278: 40899-40904, 2003.
Macip, S., Igarashi, M., Berggren, P., Yu, J., Lee, S.W., and Aaronson, S.A. Influence of induced ROS in determining p53-mediated cell fate decisions. Mol. Cell. Biol. 23: 8576-8585, 2003.
Ohtsuka, T., Jensen, M.R., Kim, H.G., and Lee, S.W. The negative role of cyclin G in ATM-dependent p53 activation. Oncogene 23: 5405-5408, 2004.
Fujiuchi N., Aglipay J.A. Ohtsuka, T., Machara, N., Sahin, F., Su, G.H., Lee, S.W., and Ouchi, T. Requirement of IFI16 for the maximal activation of p53 induced by ionizing radiation. J. Biol. Chem. 279: 20339-20344, 2004.
Ouchi M., Fujiuchi N., Ongusaha P.P., Minamishima, Y.A., Sasai K., Katayama, H., Deng, C., Sen, S., Lee, S.W., and Ouchi, T. Requirement of BRCA1 phosphorylation by aurora-A for entry into mitosis. J. Biol. Chem. 279: 19643-19648, 2004.
Ohtsuka, T., Ryu, H., Minamishima, Y.A., Macip, S., Sagara, J., Aaronson, S.A., and Lee, S.W. ASC functions as an adaptor for Bax and regulates a p53-Bax mitochondrial pathway of apoptosis. Nature Cell Biol. 6: 121-128, 2004.
Kim, K.T., Ongusaha, P.P., Hong, Y.-K., Kurdistani, S.K., Nakamura, M., Lu, K.P. and Lee, S.W. Function of Drg1/Rit42 in p53-dependent mitotic spindle checkpoint. J. Biol. Chem. 279: 38597-38602, 2004.
Ongusaha, P.P., Kwak, J.C., Zwible, A.J., Macip, S., Higashiyama, S., Taniguchi, N., Fang, L., and Lee, S.W. Heparin-binding epidermal growth factor-like growth factor HB-EGF is a potent inducer of tumor growth and angiogenesis. Cancer Res. 64: 5283-5290, 2004.
Aglipay, J.A., Lee, S.W., and Ouchi, T. ATM Activation by Ionizing Radiation Requires BRCA1-associated BAT1. Nature Cell Biology, Accepted.lism, Submitted, 2005.