The studies outlined in this application will further examine the role of the cyclin D1/cdk4 complex in hepatocyte proliferation. Cyclin D1 is an important proliferation-control gene that regulates progression through G1 phase of the cell cycle and is an oncogene in many human cancers. Our studies to date suggest that cyclin D1 is a pivotal mediator of hepatocyte proliferation in response to mitogens, extracellular matrix, and nutrients. The focus of this proposal will be to further define novel functions of cyclin D1 based on our studies in hepatocytes. We have found that in addition to promoting cell cycle progression, cyclin D1 induces hepatocyte growth (increased cell size) and global protein synthesis. Our preliminary data indicates that cyclin D1 regulates components of the translation apparatus, which is a novel finding. Since enhanced cell growth and protein synthesis are critical parts of normal and neoplastic proliferation, further studies of these pathways should provide insight into important functions of cyclin D1. We have also found that persistent cyclin D1 expression (over a matter of days) induces disturbances of the mitotic apparatus and chromosomal abnormalities. This suggests that cyclin D1 may promote genomic instability, which could be a significant component of its oncogenic effect. We therefore propose to study regulation of the mitotic apparatus and chromosome stability by cyclin D1. Our hope is that these studies will provide a better understanding of the actions of cyclin D1 in hepatocytes and other cells. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK054921-06A2
Application #
6828659
Study Section
Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
Program Officer
Serrano, Jose
Project Start
1998-09-01
Project End
2009-06-30
Budget Start
2004-09-15
Budget End
2005-06-30
Support Year
6
Fiscal Year
2004
Total Cost
$277,000
Indirect Cost
Name
Minneapolis Medical Research Fdn, Inc.
Department
Type
DUNS #
068195064
City
Minneapolis
State
MN
Country
United States
Zip Code
55415
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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