The alpha-fetoprotein (AFP) gene is an onco-fetal antigen, expressed in the developing fetus and under the pathological conditions of regeneration and tumorigenesis in the adult. The level of AFP gene expression during liver regeneration in mice is regulated by a genetically unlinked autosomal locus, Afr2. Inbred C57B1/6 mice express 8 to 10 fold less AFP during liver regeneration than wild type C3H/He mice. Lower AFP expression in regenerating liver may reflect other regulatory processes, as C57B1/6 mice are less susceptible to liver carcinogenesis than are C3H/He mice. From these and other genetic studies, it appears that the Afr2 gene is polymorphic. Since Afr2 regulates AFP expression, use of these different mouse strains provides a unique opportunity to identify a gene regulating AFP expression during liver regeneration. Using information from the Mouse Genome Project, in the first series of experiments, the Afr2 gene will be genetically mapped. Cloned DNA of this locus will be identified from a Yeast Artificial Chromosome library. Transcribed sequences will be isolated by exon-trapping and/or direction selection of cDNAs. Two criteria will be used to determine the likelihood that the transcribed sequences, as well as genes previously mapped to the locus, are Afr2: genetic linkage to the Afr2 gene and expression during liver regeneration. In the second series of experiments, a full length Afr2 cDNA clone will be prepared, transfected into a primary hepatocyte culture system, and tested for its ability to regulate AFP gene expression. Analysis of the activity of the two known Afr2 alleles will be compared. Identifying and isolating a clone of the Afr2 gene will provide a tool to study the relationships between developmental growth, controlled growth, and uncontrolled tumorigenic growth in the liver.
| Park, James K; Feuerman, Miriam H (2005) Afr2 regulation occurs cell-autonomously in vitro but is not conferred on episomal DNA in transient assays. DNA Cell Biol 24:189-98 |
| Jin, David K; Anderson, Eric C; Gilbert, Erin et al. (2005) AFP gene expression after acute diethylnitrosamine intoxication is not Afr2 regulated. Cancer Lett 220:211-20 |
| Jin, D K; Feuerman, M H (1998) Genetic mapping of Afr2 (Rif): regulator of gene expression in liver regeneration. Mamm Genome 9:256-8 |
