DMS Distinguished Lecture Series
Monday, March 31, 2003
Stanley Korsmeyer, M.D.
Harvard Medical School
"Mitochondrial Gateway to Apoptosis"
4:30 p.m. Filene Auditorium
Stanley J. Korsmeyer, M.D.
Director, Program in Molecular Oncology
Sidney Farber Professor of Pathology
Professor of Medicine, Harvard Medical School
Investigator, Howard Hughes Medical Institute
Dr. Stanley Korsmeyer is the Sidney Farber Professor of Pathology and Medicine and Howard Hughes Investigator at Dana-Farber Cancer Institute and Harvard Medical School, a member of the National Academy of Sciences, and winner of the General Motors Award in Cancer Research. Dr. Korsmeyer identified the key genetic mechanisms that govern cell death and survival and defined the role of cell death in causing cancers. Cell death, or apoptosis, is a natural, genetically programmed mechanism by which the healthy human body eliminates cells that are no longer needed. Cancer cells resist this process and live too long and also confer a cancer cell's resistance to chemotherapy and radiation therapy. Dr. Korsmeyer's pioneering work showed that cancer cells have genetic defects in this normal cellular "suicide" program that governs cell death and survival. He continues to uncover the critical steps in the cell death pathway, defining the molecular process that turns death molecules on and off. The BCL-2 gene family that Dr. Korsmeyer discovered provides a novel vantage point for the development of new anti-cancer drugs that specifically trigger cell death.
Dr. Korsmeyer's laboratory pursues a genetic approach to the regulation of programmed cell death. We are examining both the effectors and repressors of programmed cell death in mammalian cells. The developmental role as well as the biochemical function of genes that regulate cell death are being assessed.
They cloned a new gene, Bcl-2, from an inter-chromosomal translocation in human follicular B cell lymphoma. Bcl-2 is novel among proto-oncogenes in that it represses the programmed death of cells. They have isolated a series of Bcl-2 related/interacting proteins that function as pro- or anti-apoptotic molecules. This expanded Bcl-2 gene family is defined by a conserved helical domain, BH1-4, which regulates dimerization and function. Members BAX, BAD and BID interconnect with proximal death signals and undergo activating conformational changes. Transgenic and gene-ablated mice reveal critical roles of the Bcl-2 family in embryonic development and homeostosis. They are also investigating the electrophysiologic and biochemical role of the Bcl-2 family of proteins.
Two additional novel oncogenes, HOX 11 and MLL, were isolated from chromosomal breakpoints in human acute leukemia and represent homeotic genes. Hox 11 is an orphan homeobox gene located outside the mammalian Hox clusters. Hox 11 is expressed within splanchnic mesoderm and controls the genesis of the homeotic regulator in Drosphilia. MLL-deficient mice display segmental abnormalities and altered expression of downstream Hox genes. These genes provide the opportunity to decipher gene programs, which normally pattern organogenesis and segmentation and when misdirected, result in leukemic transformation.