A fundamental goal of biomedical research is to understand the processes that regulate gene expression during development and disease. The mouse alpha-fetoprotein ATP is particularly well suited for this. AFP is expressed at high levels in the fetal liver but is off in the adult liver. This is due to a 10,000 reduction in transcription during the perinatal period. The AFP gene can be reactivated in the adult liver in response to injury and in hepatocellular carcinomas. These aspects of AFP regulation-AFP activation during hepatogenesis, repression at birth, and reactivation in liver cancer and regeneration-have led to considerable interest in the control of this gene. Postnatal AFP repression is regulated in part, by a locus called Alpha-fetoprotein regulator 1 (Afr1). Afr1 was originally identified by differences in AFP levels in different mouse strains. Thus, unlike a majority of mammalian factors controlling gene expression that have been identified using biochemical approaches, Afr1 was revealed genetically. Of particular interest, Afr1 appears to regulate AFP by a mechanism that couples transcription to post-transcription events. While a connection between these events has been established in the literature, mechanisms that exist to modulate these connections are only beginning to be uncovered. Using tools of contemporary molecular genetics, we propose to identify the Afr1 gene by positional cloning. We can then understand how Afr1 regulates AFP and we are likely to learn more about the transcription/post/transcriptional connections as well as how this may be developmentally regulated to control gene expression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK059866-01A1
Application #
6471499
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Serrano, Jose
Project Start
2002-07-15
Project End
2007-06-30
Budget Start
2002-07-15
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$241,997
Indirect Cost
Name
University of Kentucky
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
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
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
Gargalovic, Peter S; Erbilgin, Ayça; Kohannim, Omid et al. (2010) Quantitative trait locus mapping and identification of Zhx2 as a novel regulator of plasma lipid metabolism. Circ Cardiovasc Genet 3:60-7
Perincheri, Sudhir; Peyton, David K; Glenn, Michelle et al. (2008) Characterization of the ETnII-alpha endogenous retroviral element in the BALB/cJ Zhx2 ( Afr1 ) allele. Mamm Genome 19:26-31
Morford, Lorri A; Davis, Christina; Jin, Lin et al. (2007) The oncofetal gene glypican 3 is regulated in the postnatal liver by zinc fingers and homeoboxes 2 and in the regenerating liver by alpha-fetoprotein regulator 2. Hepatology 46:1541-7
Spear, B T; Jin, L; Ramasamy, S et al. (2006) Transcriptional control in the mammalian liver: liver development, perinatal repression, and zonal gene regulation. Cell Mol Life Sci 63:2922-38
Perincheri, Sudhir; Dingle, R W Cameron; Peterson, Martha L et al. (2005) Hereditary persistence of alpha-fetoprotein and H19 expression in liver of BALB/cJ mice is due to a retrovirus insertion in the Zhx2 gene. Proc Natl Acad Sci U S A 102:396-401