Molecular basis of cancer in Fanconi anemia |
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The Kupfer lab works on the relationship of genomic instability and the propensity towards development of cancer. Specifically, they focus on the genetic syndrome Fanconi anemia (FA). Interestingly, children with FA are born with congenital anomalies and develop aplastic anemia and an assortment of leukemias and other cancers. FA serves as a paradigm where the disciplines of development, genetics and molecular oncology come together. Like other cancer susceptibility syndromes such as ataxia telangiectasia and xeroderma pigmentosum, FA patients exhibit a unique range of hypersensitivity to DNA damaging agents, which is the key to the biology of FA. Unlike the other syndromes, exceedingly little is known about FA. Eight complementation groups have been elucidated, with all exhibiting similar phenotypic characteristics, suggesting an interrelationship of proteins in a complex or linear pathway. To date, 6 genes have been cloned, but the encoded proteins bear no resemblance to each other or to any other known proteins. Several studies have revealed a cell cycle specific phenotype in response to DNA damage, implying a cell cycle checkpoint role for putative FA proteins. Kupfer's work has focused on protein-protein interactions and has characterized the binding of the G2/M cyclin dependent kinase, cdc2, to the first described FA protein, FANCC (Fanconi Anemia group C). Since the cloning of FANCA, he has raised antibodies against FANCA and FANCG and described the binding of FANCA, FANCC, and FANCG in a nuclear complex. Now the lab has data showing that the FA nuclear protein complex is sizable (1.5 MD) and have embarked on efforts to search for other protein partners to gain further clues on the function of the FA pathway. They have studied the subnuclear localization of FA proteins in chromatin and the nuclear matrix. This localization is inducible upon DNA damage, and the entire complex exits the nucleus at mitosis upon phosphorylation of FANCG. They are also collaborating with clinicians and epidemiologists to analyze FA genes in human cancers to assess whether FA gene mutations play a role in the pathogenesis of cancer. In addition, as a result of their interest in genomic instability, they have undertaken a collaboration with John Semmes, a former researcher in Microbiology at UVa who has recently taken a position at EVMS. They are working on the tax protein, which is encoded by the HTLV I genome. HTLV I leads to adult T cell leukemia, and the tax protein is thought to be the prime etiologic agent. Interestingly, the tax protein induces genomic instability in a way which mirrors that of FA. They believe that study of tax will give us insight into general mechanisms of genomic instability which will move the fields of both FA and HTLV I forward. They also hope to apply our findings towards the therapeutic goal of making chemotherapy more effective.
Dr. Semmes and Kupfer are also developing projects to adapt SELDI proteomics to characterize protein profiles specific to disease states. Their first efforts in this regard will entail obtaining serum from patients with Hodgkin's disease, myeloid leukemia, and myelodysplasia. They have already obtained approval from appropriate institutional committees and are in the process of having samples shipped for pilot analysis. Once they obtain pilot data, the Children's Oncology Group, of which Kupfer is a member, they will be writing their protocols for treatment and biology with the proteomics project included. At this date, the Hodgkin's Disease Biology Committee has now committed to a prospective study analyzing serum samples by proteomics.
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