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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054921-14
Application #
8281654
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Serrano, Jose
Project Start
1998-09-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
14
Fiscal Year
2012
Total Cost
$269,796
Indirect Cost
$56,624
Name
Minneapolis Medical Research Fdn, Inc.
Department
Type
DUNS #
068195064
City
Minneapolis
State
MN
Country
United States
Zip Code
55415
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
Espeillac, Catherine; Mitchell, Claudia; Celton-Morizur, Severine 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
Wang, Guo-Li; Shi, Xiurong; Salisbury, Elizabeth et al. (2007) Growth hormone corrects proliferation and transcription of phosphoenolpyruvate carboxykinase in livers of old mice via elimination of CCAAT/enhancer-binding protein alpha-Brm complex. J Biol Chem 282:1468-78
Anan, Akira; Baskin-Bey, Edwina S; Isomoto, Hajime et al. (2006) Proteasome inhibition attenuates hepatic injury in the bile duct-ligated mouse. Am J Physiol Gastrointest Liver Physiol 291:G709-16
Wang, Guo-Li; Shi, Xiurong; Salisbury, Elizabeth et al. (2006) Cyclin D3 maintains growth-inhibitory activity of C/EBPalpha by stabilizing C/EBPalpha-cdk2 and C/EBPalpha-Brm complexes. Mol Cell Biol 26:2570-82
Timchenko, Lubov T; Salisbury, Elizabeth; Wang, Guo-Li et al. (2006) Age-specific CUGBP1-eIF2 complex increases translation of CCAAT/enhancer-binding protein beta in old liver. J Biol Chem 281:32806-19

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