Induction of Apoptosis in Lymphoma Cells by Activation o

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Research: The tumor necrosis factor receptor superfamily is comprised of a number of related cell surface molecules which play crucial roles in regulating the balance between cell proliferation and cell death. Deregulation of one of these receptors, CD30, has been implicated in several disorders including Hodgkin's disease and anaplastic large cell lymphoma. Activation of CD30 by its cognate ligand or by crosslinking with agonistic antibodies can induce either proliferation or apoptotic cell death, depending upon the cellular context, although the molecular basis of this disparity is still unclear. We and others have examined the signal transduction pathways utilized by CD30. The TNF receptor-associated factors (TRAFs), which bind to elements in the cytoplasmic domains of CD30, CD40, and the type 2 TNF receptor, have been shown to activate the pleiotropic transcription factor NF kappa B, as well as the JNK (c-Jun N-terminal kinase) family of serine-threonine kinases. Both NF kappa B and JNK have been implicated in the regulation of cell survival. We have also found that activation of CD30 leads to the proteolytic degradation of TRAF2, and in anaplastic large cell lymphoma cells this is thought to lead to the failure to activate NF kappa B and the sensitization to other pro-apoptotic stimuli. Using a variety of lymphoma and leukemia cell lines, as well as a range of CD30 agonistic antibodies, were are examining the effects of CD30 activation in cell culture systems as well as in murine models. Our data suggest that CD30-directed targeting strategies may have great potential in the treatment of CD30-positive malignancies.