In our continuing collaborative efforts to understand how defects in the DNA double strand break signaling and repair pathways play a role in the generation of chromosome translocations leading to tumor formation, we have applied a variety of genomic techniques, including fluorescence in situ hybridization (FISH), spectral karyotyping (SKY), comparative genomic hybridization (CGH), immunocytochemistry (ICC), gene expression profiling (microarrays), quantitative real-time PCR (RT-PCR), epifluorescence and confocal microscopy. This fiscal year we have assisted Andre Nussenzweig (NCI) in dissecting one of the proteins involved in signaling and repair of DNA double strand breaks. The NBS1 protein, encoded by the Nijmegen breakage syndrome (NBS) gene, is part of a group of three proteins that together form the Mre11/Rad50/Nbs1 (MRN) complex. The results from our recently published paper determined that distinct domains of Nbs1 are responsible for the regulation of either irradiation-induced cell growth arrest checkpoints or cell death (apoptosis). This is important in understanding mechanistically what is occurring at the cellular level in patients suffering from Nijmegen breakage syndrome or Ataxia-Telangiectasia (AT), another disease with a very similar clinical presentation. Aberrant stabilization of the ?-catenin protein involved in the Wnt/TCF signaling pathway plays a causative role in cancers of the colon, breast and epidermal tissues. Furthermore, increased Wnt signaling has been linked with chronic myelogenous leukemia and chronic lymphocytic leukemia. Accordingly, expression of transgenic ?-catenin in many of these tissues results in the development of aggressive tumors early in life. Analyses of human cancers, mouse models and cell culture systems indicate that ?-catenin regulates the expression of a number of genes linked to cellular proliferation and cancer, including c-Myc and cyclin D1. Despite the important role that ?-catenin plays in the early stages of thymocyte development, to date aberrant ?-catenin signaling has not been directly linked to human T cell lymphomas. The molecular basis for this observation is not understood. We are collaborating with Jyoti Misra-Sen in the National Institute on Aging to examine their mouse model of ?-catenin over-expression in an effort to determine the mechanism by which developing T-cells are protected from the oncogenic affects of ?-catenin. We have determined that overexpression of ?-catenin in T cells at an early stage of development causes a phenomenon recently described as oncogene induced (cellular) senescence (OIS) provide an understanding of the underlying fail-safe mechanisms within cells that may one day lead to the identification of therapeutic targets for the treatment of cancers where ?-catenin is known to be involved.
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