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 Medi- 
cine. 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 are re- 
moved, leaving the smaller lobes completely in- 
tact, 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 ques- 
tions 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 organ 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 grov^h 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. 
Early studies identified several genes that are 
rapidly expressed in response to growth factors in 
liver cells and in commonly studied cells like 
lymphocytes and fibroblasts, respectively impor- 
tant in the immune system and scar formation. 
Many of these genes encode proteins that func- 
tion in the cell nucleus, possibly regulating the 
cascade of gene expression occurring when cells 
grow. Some of these genes have altered expres- 
sion in cancer cells, contributing to the aberrant 
proliferation. 
To isolate novel genes involved in liver cell 
growth, we have used a technique that allows 
subtraction of genes expressed in nongrowing 
cells from those expressed in growth-stimulated 
cells. Thus genes that are uniquely expressed in 
growing liver cells have been isolated and can be 
studied. We have identified approximately 50 
such genes through analysis of their sequence 
and through predictions concerning their protein 
structure. Many of the genes are expressed in 
other growing cells and seem to be pan of the 
general growth response, while some are specific 
to liver. 
In the past year, our studies have focused on 
understanding the actions of the proteins en- 
coded 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 reg- 
ulatory 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 are proteins that are se- 
creted from cells and may function to regulate 
the growth of surroimding 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 alone 
among growing cells, and we found several in 
this category, including a few that are highly ex- 
pressed. These proteins could be important in 
liver-specific growth. 
The fourth category includes several genes 
whose expression is induced in regenerating 
liver but abnormally high in the liver tumor cell 
line that grows in response to insulin, even prior 
to insulin treatment. These could function as on- 
cogenes in the liver tumor line. 
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