The Molecular Biology of Liver Regeneration 
Rebecca A. Taub, M.D. — Associate Investigator 
Dr. Taub is also Assistant Professor of Human Genetics at the University of Pennsylvania School of 
Medicine. She received her B.A. degree in biochemistry from Yale University, attended Yale University 
School of Medicine, and completed residency training in internal medicine at Yale. She was a postdoctoral 
fellow with Philip Leder at Harvard Medical School, where she later joined the Department of Internal 
Medicine as Assistant Professor before moving to Philadelphia. 
THE liver has unusual properties of regenera- 
tion. When the two largest lobes of the liver 
are removed, leaving the smaller lobes com- 
pletely intact, the remaining cells can grow and 
divide until the liver regains its former size, 
whereupon growth ceases. Many growth factors 
have been implicated in regulating this process, 
but the mechanisms remain poorly understood. 
After many years of study the same interesting 
questions about liver regeneration remain: What 
makes the liver start regenerating? What regulates 
liver growth during regeneration, allowing the 
liver to maintain its normal architecture? What 
makes the liver stop regenerating when it has re- 
gained its initial size? 
Understanding liver regeneration will help ex- 
plain how the liver responds to toxic damage or 
infections like hepatitis. Additionally, because 
increasing numbers of liver transplants are being 
performed and successful transplants require 
liver regeneration, it is essential to understand 
the biological and molecular bases for liver cell 
growth. 
My colleagues and I are interested in determin- 
ing what genes are expressed during liver regen- 
eration and how their protein products are in- 
volved in regulating the process. It is important 
to determine if these genes are identical to those 
that regulate the growth of all cells. We are study- 
ing liver cell growth in two systems: a continu- 
ously growing liver cell line that responds to in- 
sulin as a growth factor and regenerating liver 
tissue from rats. 
In our early studies, we identified more than 
40 novel genes that are rapidly expressed in re- 
sponse to growth factors in liver cells. Although 
many of the genes are expressed in other growing 
cells and seem to be part of the general growth 
response, some of the genes are specific to grow- 
ing liver. Many of these genes encode proteins 
that function in the cell nucleus, possibly regu- 
lating the cascade of gene expression occurring 
when cells grow. Some of these genes have al- 
tered expression in cancer cells, contributing to 
the aberrant proliferation. 
Our studies have focused on understanding the 
actions of the proteins encoded by some of these 
genes and their potential roles in regulation of 
liver regeneration. Because we isolated so many 
novel genes, it was important to establish criteria 
for determining which of the encoded proteins 
are likely to have important regulatory roles in 
liver regeneration. We decided to explore further 
the exact roles of novel proteins falling into four 
functional categories. 
The first category includes proteins that regu- 
late the expression of genes. Because so many 
genes need to be turned on for liver regeneration 
to proceed, proteins that regulate gene expres- 
sion are likely to be important. 
The second category includes proteins that are 
secreted from cells and may function to regulate 
the growth of surrounding cells. The liver must 
maintain its cellular architecture during regener- 
ation, and because it is made up of many different 
cell types, intercellular communications must 
exist during regeneration. Secreted proteins 
could be involved in mediating such intercellular 
signals. 
The third category includes proteins whose ex- 
pression is specific to regenerating liver and not 
other growing cells. We found several in this cate- 
gory, a few of which are highly expressed in re- 
generating liver. These proteins could have im- 
portant functions in liver-specific growth. 
The fourth category includes several genes 
whose expression is nicely induced in regenerat- 
ing liver but abnormally high in the liver tumor 
cell line that grows in response to insulin. These 
genes could be functioning as oncogenes in the 
liver tumor cell line. 
One of the novel genes that we isolated, RL/ 
IF-1 (regenerating liver inhibitory factor), en- 
codes a protein that inhibits the activity of certain 
gene-transactivating proteins in the NF-kB/RcI 
family. We examined the relative activity of 
NF-/cB/Rel proteins during liver regeneration and 
found to our surprise that although most of the 
proteins in this family remain in an inhibited or 
inactive form, one protein, PHF-1, becomes dra- 
matically active in its ability to interact with gene 
sequences within minutes after hepatectomy. 
The activation of PHF-1 is the earliest change we 
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