Event Detail (Archived)
Complex Regulation of Interferon-dependent Signaling in Cancer and Infectious Disease
Cancer Biology Lecture
- Friday Lecture Series
George R. Stark, Ph.D., Distinguished Scientist, department of cancer biology, Lerner Research Institute, Cleveland Clinic
The ability to produce and respond to Type I interferons (IFN-I) protects us from many different microorganisms and also plays diverse roles in the development and therapy of cancer. Signaling in response to IFN-I is driven by JAK-dependent tyrosine phosphorylation of STATs 1 and 2, which bind to IRF9 to form the major transcription factor ISGF3. However, additional post-translational modifications of these STATs also play crucial roles. We now find that phosphorylations of T404 and T387 of STAT2 have profound effects on IFN-I-dependent gene expression, and mice carrying T-A mutations at these sites have greatly altered antiviral defenses.
In the absence of tyrosine phosphorylation, STAT2 and IRF9 bind to each other and to DNA, activating the transcription of about 25% of the genes that respond to ISGF3. The same subset of genes is highly expressed in about half of all cancers, and their expression correlates with resistance to DNA damage. The three oligoA-synthetases (OASs), included in this subset of genes, modulate responses to cancer therapeutic agents in opposite ways. In response to DNA damage, OAS1 limits poly-ADP-ribose synthesis to protect cancer cells from death, whereas in response to azacytidine, an OAS-dependent cell death pathway is activated. We can increase or decrease OAS expression in cancer cells to facilitate better responses to different standard-of-care therapies.
George R. Stark holds a Ph.D. in Chemistry from Columbia University and completed a Postdoctoral Fellowship at the Rockefeller University. He served as Professor of Biochemistry at Stanford University from 1963 to 1983, and as the Associate Director of Research at the Imperial Cancer Research Fund in London, England from 1983 to 1992. In 1992, he became the Chair of the Lerner Research Institute of the Cleveland Clinic, serving in that role until 2002. He is currently the Distinguished Scientist of the Cleveland Clinic. Dr. Stark has authored more than 300 scholarly articles. He is a member of the U.S.A. National Academies of Sciences and Medicine, and is a fellow of the Royal Society of London.
The Stark laboratory developed important new techniques, including the Northern and Western methods. In parallel with the laboratory of Robert Schimke, they co-discovered gene amplification as a mechanism of drug resistance in cancer. They used novel genetic methods to co-discover, with the labs of Jim Darnell and Ian Kerr, the JAK-STAT signaling pathway, which mediates how mammalian cells respond to many different cytokines. Current work includes, with Mark Jackson, the development and extensive use of insertional mutagenesis as a method for discovery genetics in mammalian cells, many studies that are helping to unravel the underlying complexity in JAK-STAT signaling that is essential for precise regulation of signaling, and novel antitumor therapies based on fundamental mechanistic discoveries.
- Open to
- James Darnell
- Refreshments, 3:15 p.m. - 3:45 p.m., Abby Lounge
- Justin Sloboda
- (212) 327-7785