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.
|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|
|Wang, Jiangfang; Reuschel, Emma L; Shackelford, Jason M et al. (2011) HIV-1 Vif promotes the Gýýý- to S-phase cell-cycle transition. Blood 117:1260-9|
|Aggarwal, Priya; Vaites, Laura Pontano; Kim, Jong Kyong et al. (2010) Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase. Cancer Cell 18:329-40|
|Diehl, J Alan; Ponugoti, Bhaskar (2010) Ubiquitin-dependent proteolysis in G1/S phase control and its relationship with tumor susceptibility. Genes Cancer 1:717-724|
|Barbash, O; Egan, E; Pontano, L L et al. (2009) Lysine 269 is essential for cyclin D1 ubiquitylation by the SCF(Fbx4/alphaB-crystallin) ligase and subsequent proteasome-dependent degradation. Oncogene 28:4317-25|
|Pontano, Laura L; Diehl, J Alan (2009) DNA damage-dependent cyclin D1 proteolysis: GSK3beta holds the smoking gun. Cell Cycle 8:824-7|
|Kim, Jong Kyong; Diehl, J Alan (2009) Nuclear cyclin D1: an oncogenic driver in human cancer. J Cell Physiol 220:292-6|
|Lin, Douglas I; Aggarwal, Priya; Diehl, J Alan (2008) Phosphorylation of MCM3 on Ser-112 regulates its incorporation into the MCM2-7 complex. Proc Natl Acad Sci U S A 105:8079-84|
|Pontano, Laura L; Aggarwal, Priya; Barbash, Olena et al. (2008) Genotoxic stress-induced cyclin D1 phosphorylation and proteolysis are required for genomic stability. Mol Cell Biol 28:7245-58|
|Aggarwal, Priya; Lessie, Matthew D; Lin, Douglas I et al. (2007) Nuclear accumulation of cyclin D1 during S phase inhibits Cul4-dependent Cdt1 proteolysis and triggers p53-dependent DNA rereplication. Genes Dev 21:2908-22|
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