Department of Cell Biology Faculty

Genetic regulation of gene expression during liver regeneration and tumorigenesis

The normal adult liver has the unique ability to regenerate after poisoning, surgical resection or viral damage. However, repeated growth cycles, as observed in chronic Hepatitis B Virus (HBV) or Hepatitis C Virus infection, can result in the failure of the normal controls on liver regeneration, leading to liver cancer. The alpha-fetoprotein (AFP) gene, an oncofetal antigen, is expressed in the developing fetus and under conditions of liver 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 C57BL/6 mice express 8 to 10 fold less AFP during liver regeneration than wild type C3H/He mice. Lower AFP expression in regenerating liver reflects other regulatory processes, as C57BL/6 mice are less susceptible to liver carcinogenesis than C3H/He mice. The mechanisms that regulate growth may also regulate AFP gene expression making it an ideal surrogate marker to monitor the condition of the liver.

Using a genetic approach we have shown that the leading candidate for Afr2 is MCM8. MCM8 shares sequence homology with a family of genes that form the hexameric helicase required for DNA replication, but neither function nor role for MCM8 has been identified. The discovery that Afr2 is MCM8 suggests that regulation occurs either through DNA replication or transcription, both of which would have an impact of tumorigenesis. Based on the hypothesis that MCM8 functions an MCM family member specifically during liver regeneration, experiments to determine the activity and function of MCM8 are ongoing. Interestingly, if MCM8 functions similarly to other members of the family, the polymorphisms identified in the C3H/He allele could lead to a constitutively active gene product.

MCM8 may be one of the genes involved in liver tumorigenesis in response to chronic liver regeneration induced by HBV or HCV infection. If so, it may be possible to predict which individuals infected with HBV or HCV are more likely to develop liver cancer based on their MCM8 allele. Furthermore, MCM8 may become a target of rational drug design to prevent HBV or HCV infected individuals from developing liver cancer.

Segregation of the level of AFP gene expression in 730 identified the location of the Afr2 gene on chromosome 2 (shown top). Of the genes in the locus, only MCM8 is expressed specifically during liver regeneration (shown above)

PUBLICATIONS

• Anderson, E.C. and M.H. Feuerman. Identification of Afr2 as MCM8. Manuscript in preparation
• Park J. and M.H. Feuerman. Experimental Models of Afr2 regulation Manuscript in preparation
• Jin, D.K., E.C. Anderson, E. Gilbert and M.H. Feuerman. AFP gene expression during DEN intoxication is not Afr2 regulated. Manuscript submitted.
• Feuerman, M.H. (2002) Alpha-fetoprotein. Encyclopedia of Molecular Medicine. Editor: Thomas E. Creighton, EMBL. Editorial Board: C. Thomas Caskey, Michael R. Hayden, Haig H. Kakazian, Jr., George Klein, Hugo W. Moser, Anthony J. Pawson, Stuart H. Orkin, Bernard Roizman, R.V. Thakker, Hugh Watkins. Publisher John Wiley and Sons, New York
• Jin, D.K., J. Vacher and M.H. Feuerman (1998). Alpha-fetoprotein Sequences Mediating Afr2 Regulation during Liver Regeneration. Proceedings of the National Academy of Science 95 (15): 8768-8772.
• Jin, D.K. and M.H. Feuerman (1998). Chromosomal location of Afr2, regulator of alpha-fetoprotein gene expression during liver regeneration. Mammalian Genome. 9:256-258.

EDUCATION

Ph.D. in Biology from University of California, Irvine, 1986