We and others have reported the isolation of a clone encoding for the CCAAT/Enhancer Binding Protein (C/EBP)I3 (LAP, NF-IL6, IL6-DBP), a liver-enriched activator protein that confers liver-specific gene expression. This proposal will focus on the signal transduction pathways that modulate hepatocyte proliferation and survival through site-specific phosphorylations of C/EBP!3. We have found that transforming growth factor (TGF)-c_ and phorbol esters/protein kinaseC (PKC)-o_ mediate their effects on hepatocyte proliferation, through the activation of ribosomal S6-kinase (RSK)- 2 and phosphorylation of C/EBPI3 on its activation domain. We have established that C/EBP(3 affects the GI/S phase transition of the cell cycle. Moreover, we found that this phosphorylated C/EBP!3 plays a major role in cell survival by binding to procaspase 8 and preventing its self-cleavage and activation. Our recent discovery identifies a novel non- transcriptional role of C/EBPI3PThr z_7as the first mammalian protein acting as an inhibitor of caspases. As expected, we have found that the nonphosphorylatable C/EBP_ Ala217mutant prevents hepatocyte proliferation induced by the TGFc_/ERK/MAPK/RSK signaling cascade, while the phosphorylation mimic C/EBPI3Glu 2_zmutant blocks hepatocyte apoptosis initiated by death receptors or proteasome inhibitors (FAS/caspase 8 pathway).
The specific aims of this proposal are to assess: 1. The regulation of the cell cycle by C/EBPI3 in hepatocytes. 2. The regulation of hepatocyte proliferation and tumorigenesis in C/EBPI3 Ala2_7transgenic mice. 3. The role of C/EBP_ phosphorylation on hepatocyte survival. 217 4. The modulation of hepatocyte cell survival in C/EBPI3 Glu transgemc mice. 5. The effects of C/EBPI3Glu 217peptides on hepatocyte survival. 6. The role of C/EBPI3 phosphorylation on the development of hepatocellular carcinoma in patients. These studies are relevant to the hepatocyte proliferation and survival characteristic of many physiological and pathological conditions, including hepatocellular injury, liver regeneration and hepatocellular carcinoma.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Serrano, Jose
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Veterans Medical Research Fdn/San Diego
San Diego
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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
Buck, Martina; Chojkier, Mario (2007) C/EBPbeta associates with caspase 8 complex proteins and modulates apoptosis in hepatic stellate cells. J Clin Gastroenterol 41:S295-9
Carr, Robert A; Andre, Amy K; Chen, Ping et al. (2006) The effect of hepatic insufficiency on the safety and pharmacokinetics of paricalcitol (Zemplar). Nephron Clin Pract 103:c100-5
Chojkier, Mario (2005) Troglitazone and liver injury: in search of answers. Hepatology 41:237-46
Chojkier, Mario (2005) Inhibition of albumin synthesis in chronic diseases: molecular mechanisms. J Clin Gastroenterol 39:S143-6
Patchornik, Guy; Munson, Keith; Goldshleger, Rivka et al. (2002) The ATP-Mg2+ binding site and cytoplasmic domain interactions of Na+,K+-ATPase investigated with Fe2+-catalyzed oxidative cleavage and molecular modeling. Biochemistry 41:11740-9
Buck, M; Kim, D J; Houglum, K et al. (2000) c-Myb modulates transcription of the alpha-smooth muscle actin gene in activated hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 278:G321-8
Houglum, K; Buck, M; Kim, D J et al. (1998) TNF-alpha inhibits liver collagen-alpha 1(I) gene expression through a tissue-specific regulatory region. Am J Physiol 274:G840-7
Chojkier, M; Houglum, K; Lee, K S et al. (1998) Long- and short-term D-alpha-tocopherol supplementation inhibits liver collagen alpha1(I) gene expression. Am J Physiol 275:G1480-5
Houglum, K; Venkataramani, A; Lyche, K et al. (1997) A pilot study of the effects of d-alpha-tocopherol on hepatic stellate cell activation in chronic hepatitis C. Gastroenterology 113:1069-73

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