Normal liver has a remarkable capacity to regenerate after acute injuries that result in the loss of parenchymal cells, but this response is diminished in many liver diseases. In healthy animals, growth stimulus such as 70 percent partial hepatectomy (PH) induces differentiated hepatocytes to enter the cell cycle and rapidly restore functional liver mass. Liver regeneration has been studied extensively, and significant insight has been gained into the complex extracellular and intracellular events that control this process. However, the intracellular factors that lead to progression of hepatocytes through G1 phase of the cell cycle have not been as thoroughly characterized. Because growth stimulatory and inhibitory signals frequently control proliferation by regulating progression through G1 phase, it is salient to study the molecular control of this stage of the cell cycle. A highly conserved family of kinase complexes, consisting of cyclins and cyclin- dependent kinases (cdks), regulate the cell cycle in eukaryotic cells. Different combinations of cyclins and cdks form holoenzyme complexes which control progression through different stages of the cell cycle. The cyclin D1/cdk4 complex appears to be a critical determinant of progression through G1 phase of the cell cycle, and may be the focal point of growth stimulatory and inhibitory signals arising from extracellular stimuli. The activity of the cyclin D1/cdk4 complex is controlled by cdk-inhibitory (CKI) proteins, including p21 and p27. Our preliminary studies suggest that the cyclin D1/cdk4 complex, p21, and p27 play a role in regulating the progression of hepatocytes through G1 phase of the cell cycle in the regenerating liver. We propose to study the role of cyclins, cdks, and CKIs during hepatocyte proliferation in vitro and in the regenerating liver in vivo. Our specific goals are to: (1) Identify the mechanisms by which p21 and p27 regulate the activity of the cyclin D1/cdk4 and cyclin E/cdk2 complexes in the regenerating liver in vivo, and (2) identify the mechanisms by which transforming growth factor Beta (TGF Beta) and growth inhibitory extracellular matrix (ECM) conditions downregulate the activity of the cyclin/cdk complexes. These studies are intended to provide insight into the molecular control of liver regeneration, and to examine potential mechanisms of hepatocyte growth inhibition in human liver diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054921-05
Application #
6517541
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Serrano, Jose
Project Start
1998-09-01
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2004-06-30
Support Year
5
Fiscal Year
2002
Total Cost
$125,620
Indirect Cost
Name
Minneapolis Medical Research Fdn, Inc.
Department
Type
DUNS #
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
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
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
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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