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.
| de Leeuw, Renée; McNair, Christopher; Schiewer, Matthew J et al. (2018) MAPK Reliance via Acquired CDK4/6 Inhibitor Resistance in Cancer. Clin Cancer Res 24:4201-4214 |
| Qie, Shuo; Majumder, Mrinmoyee; Mackiewicz, Katarzyna et al. (2017) Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma. Nat Commun 8:1534 |
| Diehl, J Alan (2016) Cyclin D3: To translate or not to translate. Cell Cycle 15:3018-3019 |
| Qie, Shuo; Diehl, J Alan (2016) Cyclin D1, cancer progression, and opportunities in cancer treatment. J Mol Med (Berl) 94:1313-1326 |
| 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 15:219-220 |
| 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 |
| Li, Yan; Diehl, J Alan (2015) PRMT5-dependent p53 escape in tumorigenesis. Oncoscience 2:700-2 |
| 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 |
Showing the most recent 10 out of 35 publications
