The long-term objective of my research is the elucidation of the mechanisms whereby the cyclin D1/CDK4 kinase triggers tumorigenesis. 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. We have developed a mouse model of D1-driven B-cell lymphoma, which similar to human MCL, is genomically unstable and exhibits a paradox associated with human disease;retention of wild type p53. Because p53 functions to limit expansion of genomically unstable cells, MCL must bypass p53 without selection for loss of function mutations. We have demonstrated that cyclin D1/CDK4 activates the PRMT5 methyltransferase, and we present preliminary evidence that it can inhibit p53-dependent apoptosis providing a potential mechanism for tumor development in a wild type p53 background. MCL is also characterized by chromosomal deletions that encompass the locus encoding ATM. Loss of ATM is expected to abrogate p53 activation by DNA damage, providing a second mechanism of escape from p53 surveillance. The experiments described in the context of 3 Specific Aims will directly determine the molecular mechanisms whereby oncogenic cyclin D1 bypasses intrinsic tumor surveillance mechanisms to trigger neoplastic growth.
Aim 1 will determine the ability of PRMT5/MEP50 to cooperate with oncogenic cyclin D1T286A to induce neoplastic growth;
Aim 2 will determine the role of PRMT5/MEP50 in bypassing p53-dependent apoptosis in cells expressing nuclear cyclin D1/CDK4;
Aim 3 will assess the role of ATM, as a sensor of DNA damage, in the suppression of D1-driven malignancy.
Overexpression of cyclin D1 in human cancer occurs frequently as a consequence of mutations in the machinery that destroys the cyclin D1 protein. In order to develop effective therapies that counter these events, it is necessary to identify molecular mechanisms directed by cyclin D1 to trigger the development of neoplasia. We have identified a critical component of the machinery, the PRMT5/MEP50 arginine methyltransferase. PRMT5 not only modifies histones, but can also modify and potentially regulate p53 in response to DNA damage. The experiments described in this proposal will evaluate the biochemical and biological role of PRMT5 in tumor development and progression.
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|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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