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Bryan R. G. Williams, Ph.D., Hon. FRSNZChairman & ProfessorDepartment of Cancer Biology |
Biography
Dr Bryan R.G. Williams is Professor and Chairman in the Department of Cancer Biology at the Lerner Research Institute of the Cleveland Clinic Foundation. He is also Professor in the Department of Genetics at Case Western Reserve University, the Department of Clinical Chemistry, Cleveland State University and the Department of Chemistry, Kent State University. Dr Williams serves on the editorial boards of the Journal of Interferon and Cytokine Research and the Journal of Biological Chemistry. In 1990, Dr Williams received the Milstein Award from the International Society for Interferon Research in recognition for outstanding contributions to advancing interferons for treatment of human disease. He is past President of the International Society for Interferon and Cytokine Research and was elected Honorary Fellow, Royal Society of New Zealand in 1997. Dr Williams' scientific achievements are in the fields of interferons, genetics and molecular biology of tumor suppression. Dr Williams' laboratory investigates the molecular mechanisms of control of cellular responses to extracellular stimuli. His work focuses on the role that potential tumor suppressor genes may play in regulating cell growth, differentiation and apoptosis. He uses molecular genetic approaches to understanding the mechanisms of action of interferons, the potent cell growth regulating cytokines and for characterizing the cellular events involved in Wilms tumorigenesis. Dr Williams has published over 200 peer-reviewed manuscripts that utilize extensive molecular biology and biochemical techniques.
Research Interests
Signaling Innate Immunity and Tumor Suppression
The major theme of the Williams laboratory is investigation of the molecular mechanisms controlling cellular responses to extracellular stimuli. In particular, our work focuses on the role that potential tumor suppressor genes may play in regulating cell growth and differentiation and apoptosis. We use genetic approaches to understanding the mechanisms of action of interferons (IFNs), the potent cell-growth regulating cytokines and characterizing molecular genetic events involved in Wilms tumorigenesis.
Molecular Mechanisms of Interferon Action
Mammalian cells use complex, overlapping signal transduction pathways to sense environmental changes. When cells are subjected to viral challenge, double-stranded RNA (dsRNA), produced as part of the viral replicative cycle, stimulates cellular defense mechanisms, resulting in the production of interferon and the development of an antiviral state. We are investigating the hypothesis that specific signaling pathways are activated in this cellular response. Signaling by IFNs and other cytokines activates a cascade of kinase activities and protein-protein interactions. We have identified the stress-activated kinase p38 mitogen-activated protein (MAP) kinase as a key player in the IFN response. PKR, an IFN-induced protein kinase that is autophos-phorylated when activated by dsRNA, is an essential component of the cellular responses to extracellular stimuli. Using genetic and biochemical approaches, we have characterized the dsRNA-binding domans (dsRBD) of PKR and identified single amino acid residues that are essential for dsRNA binding. In collaboration with Dr. Jun Qin (Center for Structural Biology), we solved the structure of the dsRBD and provided a model for the activation of this kinase by dsRNA. Further structural studies, using X-ray crystallography, are under way.
PKR is able to act as a signal transducer, not only for dsRNA, but also for growth regulatory cytokines. Formation of the transcription factor NF kappa Beta is induced by dsRNA, IFN or tumor necrosis factor via a PKR-dependent pathway. In cells derived from mice in which the PKR gene has been homozygously deleted, the response of NF kappa Beta-dependent genes is deficient. PKR, a stress-responsive kinase, is required to activate p38 MAP kinase by a number of cellular stress stimuli, including those mediated by pattern recognition Toll receptors. In PKR-deleted cells, there is a deficiency in signaling via transcription factor Stat3 in response to platelet-derived growth factor. PKR is also subject to functional regulation during the cell cycle and regulates cellular responses to apoptotic stimuli.
In collaboration with Dr R.H. Silverman, we have deleted the known antiviral genes (PKR and RNASEL) from the germ line of mice and discovered that IFN is still able to offer some protection against viral infection. To elucidate the pathways involved in this response, we have used gene chip technology and identified novel IFN-regulated genes. This data, including functional categories, can be accessed at: http://www.lerner.ccf.org/cancerbio/williams/lab/. The role of these genes in IFN-repsonses is presently being investigated.
Tumor Suppressor Genes
Tumor suppressor genes are implicated in the initiation/progression of a number of cancers. Wilms tumor (WT), a pediatric nephroblastoma, is associated with the deletion or mutation of the WT1 gene residing at band p13 on chromosome 11. The expression pattern of WT, supported by mutational analyses in human disease and mouse models, suggests a role in development of the genitourinary system, in tumors originating from these tissues, and in the etiology of some leukemias and possibly breast cancer. We are investigating the upstream regulators and downstream targets of WT1 using custom cDNA arrays produced in our laboratory to better understand its role in development and cancer.
Area of general research interest:
Molecular mechanisms of control of cellular proliferation and resistance to disease.
Current programs:
- Signal transduction by interferons and cytokines.
- Role of tumor suppressor genes in differentiation and development.
- Molecular genetics of human cancers.
- Searchable Dataset: Identification of genes differentially regulated by interferon alpha beta or gamma using oligonucleotide arrays
The Williams Laboratory
Project Scientist
- Pieter Faber, Ph.D.
- Xavier Lee, Ph.D.
Research Associates
- Patricia Stanhope-Baker, Ph.D.
- Whitmore, Mark, Ph.D.
- Rongzhi Wu, Ph.D.
- Maryam Zamanian-Daryoush, Ph.D.
Research Fellows
- Joao Marques, Ph.D.
- Anthony Sadler, Ph.D.
Special Research Fellow
- Bertrand Frottier, M.S.
Lead Technologist
- Patricia Kessler, M.S.
Technologists
- Jeanna M. Guenther, B.S.
- Die Wang, B.S.
Graduate Students
- Arindam Chakrabarti, M.S. (Kent State)
- Michelle Holko, B.S. (CWRU Genetics)
- Wenliang Li, B.S. (CWRU Genetics)
- Carol Ann Sledz, B.S. (CWRU Molecular Virology)
Collaborators
- Robert Silverman, Ph.D., Dept. of Cancer Biology, CCF
- Jun Qin, Ph.D., Center for Structural Biology, CCF
- Ganes Sen Ph.D., Dept. of Molecular Biology, CCF
- Khalid Khabar Ph.D., King Faisal Specialist Hospital & Research Center, Riyadh, Saudia Arabia
- Herman Yeger, Ph.D., Hospital for Sick Children, Toronto, Ontario, Canada