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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA093237-10
Application #
8014986
Study Section
Special Emphasis Panel (ZRG1-MONC-U (01))
Program Officer
Hildesheim, Jeffrey
Project Start
2001-07-01
Project End
2012-09-29
Budget Start
2011-02-01
Budget End
2012-09-29
Support Year
10
Fiscal Year
2011
Total Cost
$282,349
Indirect Cost
Name
University of Pennsylvania
Department
Biology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Cárdenas, César; Müller, Marioly; McNeal, Andrew et al. (2016) Selective Vulnerability of Cancer Cells by Inhibition of Ca(2+) Transfer from Endoplasmic Reticulum to Mitochondria. Cell Rep 15:219-20
Diehl, J Alan (2016) Cyclin D3: To translate or not to translate. Cell Cycle 15:3018-3019
Lian, Zhaorui; Lee, Eric K; Bass, Adam J et al. (2015) FBXO4 loss facilitates carcinogen induced papilloma development in mice. Cancer Biol Ther 16:750-5
Yoshida, Akihiro; Diehl, J Alan (2015) CDK4/6 inhibitor: from quiescence to senescence. Oncoscience 2:896-7
Augello, Michael A; Berman-Booty, Lisa D; Carr 3rd, Richard et al. (2015) Consequence of the tumor-associated conversion to cyclin D1b. EMBO Mol Med 7:628-47
Li, Yan; Chitnis, Nilesh; Nakagawa, Hiroshi et al. (2015) PRMT5 is required for lymphomagenesis triggered by multiple oncogenic drivers. Cancer Discov 5:288-303
Li, Yan; Diehl, J Alan (2015) PRMT5-dependent p53 escape in tumorigenesis. Oncoscience 2:700-2
Vaites, L P; Lian, Z; Lee, E K et al. (2014) ATM deficiency augments constitutively nuclear cyclin D1-driven genomic instability and lymphomagenesis. Oncogene 33:129-33
Schoppy, David W; Ragland, Ryan L; Gilad, Oren et al. (2012) Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR. J Clin Invest 122:241-52
Valvezan, Alexander J; Zhang, Fang; Diehl, J Alan et al. (2012) Adenomatous polyposis coli (APC) regulates multiple signaling pathways by enhancing glycogen synthase kinase-3 (GSK-3) activity. J Biol Chem 287:3823-32

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