The studies proposed in this application will further investigate the role of cyclin D1 in hepatocyte proliferation, growth, metabolism and gene regulation. Cyclin D1 is a pivotal cell cycle control protein and an important oncogene that is over-expressed in many human cancers. Our previous studies have demonstrated that cyclin D1 plays a key role in hepatocyte proliferation. The studies outlined here will further define the mechanisms underlying the role of cyclin D1 in cell cycle progression, growth, and novel functions uncovered in our laboratory - the regulation of hepatic metabolism and the control of mRNA stability. We will define the role of functional domains of cyclin D1 in each of these processes. Our approach will involve the extensive use of transfection techniques and transgenic mice, and are intended to provide a significant advance in our understanding of the role of cyclin D1 in vivo. We expect that these studies will be highly relevant to the processes of liver regeneration, hepatic metabolism, and carcinogenesis.
This proposal examines the cellular actions of cyclin D1, a critical cell cycle control protein that plays a role in many human cancers. These studies will provide a better understanding of mechanisms that control liver regeneration and contribute to the development of cancer. This data will help to define potential targets for therapies for liver diseases and cancer.
|Kamarajugadda, Sushama; Becker, Jennifer R; Hanse, Eric A et al. (2016) Cyclin D1 represses peroxisome proliferator-activated receptor alpha and inhibits fatty acid oxidation. Oncotarget 7:47674-47686|
|Nakamura, Ikuo; Fernandez-Barrena, Maite G; Ortiz-Ruiz, Maria C et al. (2013) Activation of the transcription factor GLI1 by WNT signaling underlies the role of SULFATASE 2 as a regulator of tissue regeneration. J Biol Chem 288:21389-98|
|Hanse, Eric A; Mashek, Douglas G; Becker, Jennifer R et al. (2012) Cyclin D1 inhibits hepatic lipogenesis via repression of carbohydrate response element binding protein and hepatocyte nuclear factor 4?. Cell Cycle 11:2681-90|
|Loponen, Heidi; Ylikoski, Jukka; Albrecht, Jeffrey H et al. (2011) Restrictions in cell cycle progression of adult vestibular supporting cells in response to ectopic cyclin D1 expression. PLoS One 6:e27360|
|Shu, Jingmin; Kren, Betsy T; Xia, Zhilian et al. (2011) Genomewide microRNA down-regulation as a negative feedback mechanism in the early phases of liver regeneration. Hepatology 54:609-19|
|Espeillac, Catherine; Mitchell, Claudia; Celton-Morizur, Séverine et al. (2011) S6 kinase 1 is required for rapamycin-sensitive liver proliferation after mouse hepatectomy. J Clin Invest 121:2821-32|
|Mullany, Lisa K; Hanse, Eric A; Romano, Andrea et al. (2010) Cyclin D1 regulates hepatic estrogen and androgen metabolism. Am J Physiol Gastrointest Liver Physiol 298:G884-95|
|Hanse, Eric A; Nelsen, Christopher J; Goggin, Melissa M et al. (2009) Cdk2 plays a critical role in hepatocyte cell cycle progression and survival in the setting of cyclin D1 expression in vivo. Cell Cycle 8:2802-9|
|Mullany, Lisa K; White, Peter; Hanse, Eric A et al. (2008) Distinct proliferative and transcriptional effects of the D-type cyclins in vivo. Cell Cycle 7:2215-24|
|Mullany, Lisa K; Nelsen, Christopher J; Hanse, Eric A et al. (2007) Akt-mediated liver growth promotes induction of cyclin E through a novel translational mechanism and a p21-mediated cell cycle arrest. J Biol Chem 282:21244-52|
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