Biology of the liver is regulated by a complex network of many signal transduction pathways. Theunderstanding of molecular basis of biological processes in the liver is highly significant for the support ofhealthy life in humans. This renewal of R01 application investigates molecular mechanisms of liver growthand differentiation, liver regeneration after surgical resections and liver recovery after chemical injuries. Twomembers of C/EBP family, C/EBPa and C/EBPb, are critical regulators of liver biology and liver functions. Inthe course of previous studies, we found that phosphorylation of C/EBPa at S193 increases its hetero-dimerization with C/EBPb and subsequent interactions of the C/EBPa/b dimers with chromatin remodelingproteins p300 and HDAC1. While C/EBP-p300 complexes activate promoters of target genes, C/EBP-HDAC1complexes mainly repress the promoters. Therefore, amounts of C/EBPa/b-p300 and C/EBPa/b-HDAC1complexes are changed during distinct biological processes in appropriate ratios. The main hypothesis ofthis application is that the network of C/EBP proteins and chromatin remodeling proteins regulatespost-natal liver growth and differentiation, liver regeneration after surgical resections and liver injuryafter CCl4 treatments. We generated 4 genetically modified mouse models: C/EBPa-S193D mice (phosphor-mimicking mutation), C/EBPa-S193A mice (no phosphorylation on S193), transgenic mice which expressdominant negative p300 (dnp300) and double knockin-transgenic S193D-dnp300 mice. We found thatC/EBPa-S193A mutant does not interact with HDAC1; however, S193D mutation increases interactions ofC/EBPa with HDAC1. Our data show that proliferation of the liver is inhibited in S193D mice, while liverproliferation is increased in S193A mice.
Specific Aim 1 will test the hypothesis that a balance of C/EBPa/b-p300 and C/EBPa/b-HDAC1 complexes is required for normal post-natal liver development.
Specific Aim 2 will test the hypothesis that C/EBPa controls entry of hepatocytes into cell cycle and termination of liverregeneration after partial hepatectomy (PH) through interactions with HDAC1.
Specific Aim 3 will examine thehypothesis that severe liver injury in young S193D and old WT mice after treatments with CCl4 is caused byC/EBPa/b-HDAC1-mediated repression of telomere reverse transcriptase, TERT.
This aim i s based on theobservations that a) CCl4 causes severe liver damage and increased apoptosis in young S193D and old WTmice (both have high levels of C/EBPa-HDAC1 complexes); b) that basal levels of TERT are reduced inyoung S193D mice and in old WT mice; and c) that the TERT promoter contains binding sites for C/EBPproteins. In summary, the elucidation of the mechanisms of liver proliferation during post-natal developmentand after surgical resections as well as mechanisms of liver recovery after drug-mediated injury will have highimpact on the field of liver biology and will provide a step for the further studies in clinical settings.

Public Health Relevance

The application examines the mechanisms of liver growth and differentiation after birth and liver regenerationafter surgical resections and after injury. The elucidation of these mechanisms is required to developapproaches to improve liver functions after surgical resections and after liver injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
7R01GM055188-17
Application #
8853633
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Gaillard, Shawn R
Project Start
1997-09-01
Project End
2014-11-30
Budget Start
2014-07-01
Budget End
2014-11-30
Support Year
17
Fiscal Year
2014
Total Cost
$101,400
Indirect Cost
$36,400
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Jin, Jingling; Hong, Il-Hwa; Lewis, Kyle et al. (2015) Cooperation of C/EBP family proteins and chromatin remodeling proteins is essential for termination of liver regeneration. Hepatology 61:315-25
Jin, Jingling; Iakova, Polina; Breaux, Meghan et al. (2013) Increased expression of enzymes of triglyceride synthesis is essential for the development of hepatic steatosis. Cell Rep 3:831-43
Jiang, Yanjun; Jin, Jingling; Iakova, Polina et al. (2013) Farnesoid X receptor directly regulates xenobiotic detoxification genes in the long-lived Little mice. Mech Ageing Dev 134:407-15
Jin, Jingling; Iakova, Polina; Jiang, Yanjun et al. (2011) The reduction of SIRT1 in livers of old mice leads to impaired body homeostasis and to inhibition of liver proliferation. Hepatology 54:989-98
Jones, Karlie; Jin, Bingwen; Iakova, Polina et al. (2011) RNA Foci, CUGBP1, and ZNF9 are the primary targets of the mutant CUG and CCUG repeats expanded in myotonic dystrophies type 1 and type 2. Am J Pathol 179:2475-89
Haefliger, Simon; Klebig, Christiane; Schaubitzer, Kerstin et al. (2011) Protein disulfide isomerase blocks CEBPA translation and is up-regulated during the unfolded protein response in AML. Blood 117:5931-40
Iakova, Polina; Timchenko, Lubov; Timchenko, Nikolai A (2011) Intracellular signaling and hepatocellular carcinoma. Semin Cancer Biol 21:28-34
Lin, Qiushi; Chen, Dahu; Timchenko, Nikolai A et al. (2010) SKI promotes Smad3 linker phosphorylations associated with the tumor-promoting trait of TGFbeta. Cell Cycle 9:1684-9
Willis-Martinez, Danielle; Richards, Hunter W; Timchenko, Nikolai A et al. (2010) Role of HDAC1 in senescence, aging, and cancer. Exp Gerontol 45:279-85
Harrison-Findik, Duygu Dee; Klein, Elizabeth; Crist, Callie et al. (2007) Iron-mediated regulation of liver hepcidin expression in rats and mice is abolished by alcohol. Hepatology 46:1979-85

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