Scott Lowe, Ph.D., Cold Spring Harbor Laboratory

Bcl-2 blocks chemotherapy induced apoptosis in vivo. Mice harboring control and Bcl-2 overexpressing lymphomas were treated with the chemotherapeutic drug cyclophosphamide and lymph nodes were removed 4 hours later. Shown are sections for each tumor examined for GFP expression, the frequency of apoptosis (TUNEL), and overall histological appearance (H/E staining). The ability of Bcl-2 to abrogate the short-term apoptotic response to chemotherapy correlates with a poor long-term outcome.
From Schmitt et al. Nat. Med. 6: 1029 (2000).

Scott Lowe
Professor
Investigator, Howard Hughes Medical Institute
Ph.D., Massachusetts Institute of Technology, 1994
Modulation of apoptosis; chemosensitivity; senescence by cancer genes

email lowe@cshl.edu, phone (516) 367-8406, fax (516) 367-8454

Apoptosis is a genetically-controlled form of cell death that is important for normal development and tissue homeostasis. Senescence produces "genetic death" in that the senescent cell is incapable of further propagation. Both processes are frequently disrupted in cancer cells, implying that each can limit tumor development. Moreover, radiation and many chemotherapeutic agents can induce either apoptosis or senescence, and there is substantial evidence that the integrity of these programmed responses influences the outcome of cancer therapy in patients. The goal of our research is to understand how cancer genes control apoptosis and senescence in normal cells, and how mutations that disrupt these processes impact tumor development and therapy.

Much of our research approach stems from efforts to understand p53 tumor suppressor gene action. p53 functions as a key component of several cellular stress responses and, as such, acts at a variety of levels to protect against cancer. Our laboratory previously identified factors that act upstream or downstream of p53 and is assembling these components into a tumor suppressor "network." We are currently interested in how oncogenes or DNA damaging agents signal p53 and how p53 executes a biological response. To address these and other issues, we have developed new animal models to explore p53 action in vivo to identify new oncogenes and tumor suppressor genes through comparative oncogenomics approaches, and to control endogenous gene expression using stable and conditional RNA interference.

Selected Publications

Dickins, R.A., McJunkin, K., Hernando, E., Premsrirut, P.K., Krizhanovsky, V., Burgess, D.J., Kim S.Y., Cordon-Cardo, C., Zender, L., Hannon, G.J., and Lowe S.W. 2007. Tissue-specific and reversible RNAi in transgenic mice. Nat Genet. 39: 914-921

Xue, W., Zender, L., Miething, C., Dickins, R.A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., Lowe, S.W. 2007. Senescence and tumour clearance is triggered by 53 restoration in murine liver carcinomas. Nature 445: 656–660.

Zender, L., Spector, M.S., Xue, W., Flemming, P., Cordon-Cardo, C., Silke, J., Fan, S.-T., Luk, J.M., Wigler, M., Hannon, G.J., Mu, D., Lucito, R., Powers, S., and Lowe, S.W. 2006. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125: 1253–1267.

Narita, M., Narita, M., Krizhanovsky, V., Nunez, S., Chicas, A., Hearn, S.A., Myers, M.P., and Lowe, S.W. 2006. A novel role for high-mobility group A proteins in cellular senescence and heterochromatin formation. Cell 126: 503–514.

Hemann, M.T., Bric, A., Teruya-Feldstein, J., Herbst, A., Nilsson, J.A., Cordon-Cardo, C., Cleveland, J.L., Tansey, W.P., and Lowe, S.W. 2005. Evasion of the p53 tumor surveillance network by tumor-derived MYCmutants. Nature 436: 807–811.