in human keratin 14 genes of epidermolysis bul- 
losa simplex patients: genetic and functional anal- 
yses. Ce// 66:1301-1311. 
Coulombe, P.A., Hutton, M.E., Vassar, R., and 
Fuchs, E. 1991. A function for keratins and a 
common thread among different types of epider- 
molysis bullosa simplex diseases. / Cell Biol 
115:1661-1674. 
Fuchs, E. 1991. Keratin genes, epidermal differen- 
tiation and animal models for the study of human 
skin diseases. Biochem Soc Trans 19:1112- 
1115. 
Fuchs, E. 1991. Threads between useful and use- 
less. Curr Biol 1:284-287. 
Fuchs, E., and Coulombe, P.A. 1992. Of mice and 
men: genetic skin diseases of keratin. Cell 69: 
899-902. 
Fuchs, E., Esteves, R.A., and Coulombe, P.A. 1992. 
Transgenic mice expressing a mutant keratin 10 
gene reveal the likely genetic basis for epidermo- 
lytic hyperkeratosis. Proc Natl Acad Sci USA 
89:6906-6910. 
Leask, A., Byrne, C, and Fuchs, E. 1991. Tran- 
scription factor AP2 and its role in epidermal- 
specific gene expression. Proc Natl Acad Sci USA 
88:7948-7952. 
Letai, A., Coulombe, P.A., and Fuchs, E. 1992. Do 
the ends justify the mean? Proline mutations at the 
ends of the keratin coiled-coil rod segment are 
more disruptive than internal mutations. / Cell 
Biol 116:1181-1195. 
Turksen, K., Kupper, T., Degenstein, L., Williams, 
I., and Fuchs, E. 1992. Interleukin 6: insights to 
its function in skin by overexpression in trans- 
genic mice. Proc Natl Acad Sci USA 89:5068- 
5072. 
VIRAL REPLICATION AND PATHOGENESIS 
Donald E. Ganem, M.D., Associate Investigator 
Dr. Ganem's laboratory is interested in the molec- 
ular mechanisms by which human and animal viral 
pathogens replicate in their hosts and cause disease. 
Work of this group centers around the hepatitis B 
viruses (hepadnaviruses), small hepatotropic DNA 
viruses that produce acute and chronic liver injury 
and are strongly associated with the development of 
liver cancer. 
Hepadnaviruses and Liver Cancer 
Persistent infection from birth with human hepati- 
tis B virus (HBV) results in a 100-fold increase in 
the risk of developing hepatocellular carcinoma 
(HCC). The molecular mechanism by which HBV 
engenders HCC is unknown and constitutes one of 
the great unsolved puzzles of human cancer biol- 
ogy. Tumors typically arise ~30 years after the on- 
set of infection. In most tumor samples, active viral 
replication (often seen in the surrounding nontu- 
morous liver) is not observed; instead, integrated 
copies of the HBV genomes are found. Tumors are 
clonal with respect to these insertions, indicating 
that integration preceded or coincided with the 
final transforming event leading to outgrowth of the 
mass. 
Opinion is divided as to the importance of these 
integrants in the pathogenesis of human HCC. Cer- 
tainly one possible role for such integrants is in the 
disruption or activation of flanking host genes. 
Work in Dr. Ganem's laboratory and in the group of 
Dr. Marie-Annick Buendia in Paris has established a 
central role for viral integration in the pathogenesis 
of HCC in infection by woodchuck hepatitis virus 
(WHV) . WHV is a close animal relative of HBV that 
shares with it DNA sequence homology, antigenic 
cross-reactivity, and many key biological features. 
WHV induces HCC in 100% of animals infected 
from birth, with tumors beginning in young adult- 
hood. About 40% of these tumors can be shown to 
harbor viral insertions flanking the N-myc cellular 
proto-oncogene. This gene is normally silent in 
adult liver, but viral insertion leads to the accumu- 
lation of abundant N-myc mRNA. Insertions gener- 
ally occur within 2-3 kb of the gene but can be 
either 3' or 5' to the locus. 
N-mj'c loci activated this way are now being 
cloned, with the plan being to establish them in 
transgenic mice, thereby providing a system to 
prove that these rearrangements are on the pathway 
to HCC formation. Attempts are also being made to 
determine if other cellular loci are regularly 
disrupted by viral integration: the goal is to use 
WHV sequences as a "transposon tag" to clone other 
host loci involved in the control of hepatocyte 
proliferation. 
Another mammalian virus, the ground squirrel 
hepatitis virus (GSHV) , also induces HCC in its natu- 
ral host, although with a lower incidence and with 
56 
