Nuclear Accumulation of Cyclin D1 and Oncogenesis

University Of Pennsylvania, Philadelphia PA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): The long-term objective of my research centers on elucidation of the mechanisms whereby extra-cellular signals are sensed by the cell cycle machinery and regulate cell cycle progression in normal versus tumor cells. This information will provide the framework necessary to elucidate how growth regulatory pathways are subverted in neoplasia. Our current studies focus on how growth-signaling pathways regulate the mitogenically responsive D-type cyclins and more specifically how these pathways regulate accumulation of an active, nuclear cyclin D1-dependent kinase in normal versus cancerous cells. The noted overexpression of cyclin D1 in multiple human cancers highlights the importance of elucidating the mechanisms that regulate cyclin D1 activity. Of the various cancers in which deregulated cyclin D1 activity is implicated, mantle cell lymphoma (MCL) is one of the most devastating. Cyclin D1 is aberrantly expressed in MCL due to the 11:14 chromosomal translocation. MCL represents a distinct category of B-cell lymphoma that presents as a disseminated disease with involvement of bone marrow, spleen, and, sometimes, gastrointestinal tract. Because there is no effective treatment, MCL has a poor prognosis with an average survival of 3.5 years post-diagnosis. Although cyclin D1 is overexpressed in MCL, have yet to establish any mouse models that recapitulate cyclin D1-dependent lymphomagenesis. We propose this reflects inadequate understanding of how cyclin D1 is regulated post-translationally in normal versus tumor cells. Indeed we have previously demonstrated that cyclin D1-dependent cell transformation in vitro depends upon its nuclear retention during S-phase. We therefore generated transgenic mice wherein a nuclear export defective, and thus constitutively nuclear, cyclin D1 allele is targeted to lymphoid compartments. Expression of this cyclin D1 allele specifically promotes B-cell lymphoma. Lymphoma development correlates with p53 loss. We hypothesize that lymphomagenesis triggered by constitutively nuclear cyclin D1 mutants is restricted by p53- dependent apoptosis and therefore dependent upon inactivation of p53. The experiments described in this proposal will determine the mechanisms whereby D1-T286A expression triggers p53 activation, establish the role of p53 in tumor suppression, and evaluate the contribution of nuclear cyclin D1 isoforms to growth and proliferation of mantle cell lymphoma-derived cells. [unreadable] [unreadable] [unreadable]