We and others have reported the isolation of a clone encoding for the CCAAT/Enhancer Binding Protein (C/EBP)(, and we have established that C/EBP( is a critical modulator of both gene expression and the G1/S phase transition of the cell cycle. Activation of ribosomal S6-kinase (RSK)- 2 and phosphorylation of C/EBP( on its activation domain plays a major role in cell survival, at least in part, by binding to the procaspase 8 complex and preventing its self-cleavage and activation. Our recent discovery identifies a novel non-transcriptional role of C/EBP( acting as an inhibitor of the caspase 8 pathway. It remains to be determined what are the mechanisms involved, and whether this inhibition is direct and/or indirect. We have determined that the MAPK-RSK-C/EBP( signaling cascade modulates expression of FLIPL, a critical inhibitor of procaspase 8. Also, we have found that C/EBP( associates with FLIPL and that this association is down-regulated by FAS signaling. As expected, the non-phosphorylatable C/EBP(Ala217 mutant prevents stellate cell activation induced by the collagen type I matrix or growth factor/MAPK/RSK signaling cascade, while the phosphorylation mimic C/EBP(Glu217 mutant blocks stellate cell apoptosis initiated by death receptors or proteasome inhibitors (caspase 8 pathway). This proposal will study the mechanism(s) by which C/EBP( modulates the extrinsic apoptotic pathway in hepatic stellate cells. ? ? The specific aims of this proposal are to assess: ? ? 1. The regulation of FLIPL activity by MAPK-RSK-C/EBP( signaling in stellate cells. ? 2. The role of C/EBP( phosphorylation on stellate cell survival. ? 3. The modulation of stellate cell survival in C/EBP(Glu217 transgenic mice. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK038652-21
Application #
7431759
Study Section
Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
Program Officer
Doo, Edward
Project Start
1987-07-01
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
21
Fiscal Year
2008
Total Cost
$315,322
Indirect Cost
Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
933863508
City
San Diego
State
CA
Country
United States
Zip Code
92161
Buck, Martina; Solis-Herruzo, Jose; Chojkier, Mario (2016) C/EBP?-Thr217 Phosphorylation Stimulates Macrophage Inflammasome Activation and Liver Injury. Sci Rep 6:24268
Buck, Martina; Garcia-Tsao, Guadalupe; Groszmann, Roberto J et al. (2014) Novel inflammatory biomarkers of portal pressure in compensated cirrhosis patients. Hepatology 59:1052-9
Chojkier, Mario; Elkhayat, Hisham; Sabry, Dina et al. (2012) Pioglitazone decreases hepatitis C viral load in overweight, treatment naïve, genotype 4 infected-patients: a pilot study. PLoS One 7:e31516
Buck, Martina; Chojkier, Mario (2011) C/EBP?-Thr217 phosphorylation signaling contributes to the development of lung injury and fibrosis in mice. PLoS One 6:e25497
Ramamoorthy, Sonia; Donohue, Michael; Buck, Martina (2009) Decreased Jun-D and myogenin expression in muscle wasting of human cachexia. Am J Physiol Endocrinol Metab 297:E392-401
Feldstein, Ariel; Kleiner, David; Kravetz, David et al. (2009) Severe hepatocellular injury with apoptosis induced by a hepatitis C polymerase inhibitor. J Clin Gastroenterol 43:374-81
Buck, Martina (2008) Direct infection and replication of naturally occurring hepatitis C virus genotypes 1, 2, 3 and 4 in normal human hepatocyte cultures. PLoS One 3:e2660
Buck, Martina (2008) A novel domain of BRCA1 interacts with p53 in breast cancer cells. Cancer Lett 268:137-45
Buck, Martina (2008) Targeting ribosomal S-6 kinase for the prevention and treatment of liver injury and liver fibrosis. Drug News Perspect 21:301-6
Buck, Martina; Chojkier, Mario (2007) C/EBPbeta phosphorylation rescues macrophage dysfunction and apoptosis induced by anthrax lethal toxin. Am J Physiol Cell Physiol 293:C1788-96

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