Mammalian liver development requires the sequential activation of genes in a highly ordered manner. Once activated, levels of gene expression in the liver must continually be responsive to extracellular signals in order for organisms to maintain physiological homeostasis. We have been studying the mouse alpha- fetoprotein (AFP) gene as a model of liver-specific gene regulation. These studies have focused on the AFP enhancer region. More recently, we have become increasingly interested regulation of all genes in the albumin-AFP gene family. One main goal of this proposal is to investigate the role of the AFP enhancers in the control of this gene family in the liver. Since AFP is activated in the fetal liver, shut-off at birth, and reactivated in models of liver damage and liver cancer, these studies should help elucidate the basis of transcriptional changes that occur during liver damage and hepatocarcinogenesis. We are also interested in studying the process of zonal regulation in the adult liver. Zonal gene expression is a mechanism that allows different subpopulations of hepatocyte in the liver to carry out distinct metabolic activities. The zonal gene regulation can be disrupted in damaged liver and in neoplastic liver cells. Since zonal gene regulation is essential for the liver to carry out its normal function, it is important to understand the basis for this control in the normal and diseased liver.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
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Serrano, Jose
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University of Kentucky
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Jiang, Jieyun; Creasy, Kate Townsend; Purnell, Justin et al. (2017) Zhx2 (zinc fingers and homeoboxes 2) regulates major urinary protein gene expression in the mouse liver. J Biol Chem 292:6765-6774
Creasy, Kate T; Jiang, Jieyun; Ren, Hui et al. (2016) Zinc Fingers and Homeoboxes 2 (Zhx2) Regulates Sexually Dimorphic Cyp Gene Expression in the Adult Mouse Liver. Gene Expr 17:7-17
Zhang, Hai; Cao, Dongmei; Zhou, Luting et al. (2015) ZBTB20 is a sequence-specific transcriptional repressor of alpha-fetoprotein gene. Sci Rep 5:11979
Kril, Liliia M; Vilchez, Valery; Jiang, Jieyun et al. (2015) N-Aryl benzenesulfonamide inhibitors of [3H]-thymidine incorporation and ?-catenin signaling in human hepatocyte-derived Huh-7 carcinoma cells. Bioorg Med Chem Lett 25:3897-9
Galuppo, Roberto; Maynard, Erin; Shah, Malay et al. (2014) Synergistic inhibition of HCC and liver cancer stem cell proliferation by targeting RAS/RAF/MAPK and WNT/?-catenin pathways. Anticancer Res 34:1709-13
Gedaly, Roberto; Galuppo, Roberto; Daily, Michael F et al. (2014) Targeting the Wnt/?-catenin signaling pathway in liver cancer stem cells and hepatocellular carcinoma cell lines with FH535. PLoS One 9:e99272
Yue, Xuetian; Zhang, Zhenyu; Liang, Xiaohong et al. (2012) Zinc fingers and homeoboxes 2 inhibits hepatocellular carcinoma cell proliferation and represses expression of Cyclins A and E. Gastroenterology 142:1559-70.e2
Clinkenbeard, Erica L; Butler, James E; Spear, Brett T (2012) Pericentral activity of alpha-fetoprotein enhancer 3 and glutamine synthetase upstream enhancer in the adult liver are regulated by ?-catenin in mice. Hepatology 56:1892-901
Liu, Hua; Ren, Hui; Spear, Brett T (2011) The mouse alpha-albumin (afamin) promoter is differentially regulated by hepatocyte nuclear factor 1? and hepatocyte nuclear factor 1?. DNA Cell Biol 30:137-47
Peterson, Martha L; Ma, Chunhong; Spear, Brett T (2011) Zhx2 and Zbtb20: novel regulators of postnatal alpha-fetoprotein repression and their potential role in gene reactivation during liver cancer. Semin Cancer Biol 21:21-7

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