Our long-term objective is to determine how extra-cellular signals are sensed by the cell cycle machine and then transmitted into regulated cell cycle progression.
The specific aims of this proposal are to define the role o the site-specific phosphorylation in the regulation of cyclin D1 nuclear import and export, to determine the relationship between cyclin D1 localization and the proteolysis, to explore the potential oncogenicity of cyclin D1 proteins that are constitutively nuclear, and to determine the mechanism of cyclin D1-dependent transformation. Interspecies heterokaryon assays will be used to examine the parameters that regulate cyclin D1 nuclear export, and in vitro nuclear import assays will be used to directly determine the mechanism(s) of cyclin D1 nuclear import. The necessity of nuclear export for efficient cyclin Dl proteolysis will also be determined using both in vitro and in vivo techniques. Finally, we will test the hypothesis that failure to remove cyclin Dl from the nucleus during S-phase is critical for normal cellular proliferation by creating mice carrying the cyclin D1 variant, D 1-T286A, whose expression is controlled by the immunoglobulin intron enhancer element, E(mu). The subversion of normal growth signaling pathways is a hallmark of neoplasia, and the capacity of cyclin D1 to act as a mitogenic sensor that integrates growth factor signals into cell cycle progression makes it a frequent target in Cancer. The studies proposed will identify the regulatory mechanisms that determine cyclin D1 subcellular localization, determine the role of localization in cyclin D1 accumulation, and demonstrate how cells constrain cyclin D1 activity, thereby preventing neoplasia.
|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|
|Li, Yan; Chitnis, Nilesh; Nakagawa, Hiroshi et al. (2015) PRMT5 is required for lymphomagenesis triggered by multiple oncogenic drivers. Cancer Discov 5:288-303|
|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|
Showing the most recent 10 out of 35 publications