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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA093237-11
Application #
8443265
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Hildesheim, Jeffrey
Project Start
2001-07-01
Project End
2017-07-31
Budget Start
2012-09-30
Budget End
2013-07-31
Support Year
11
Fiscal Year
2012
Total Cost
$297,661
Indirect Cost
$111,623
Name
University of Pennsylvania
Department
Biology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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 15:219-20
Li, Yan; Diehl, J Alan (2015) PRMT5-dependent p53 escape in tumorigenesis. Oncoscience 2:700-2
Li, Yan; Chitnis, Nilesh; Nakagawa, Hiroshi et al. (2015) PRMT5 is required for lymphomagenesis triggered by multiple oncogenic drivers. Cancer Discov 5:288-303
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
Yoshida, Akihiro; Diehl, J Alan (2015) CDK4/6 inhibitor: from quiescence to senescence. Oncoscience 2:896-7
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

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