volve factors that circulate between cells and mem- 
brane receptors that are coupled to signaling ma- 
chinery inside the cell. The signals carried by 
growth-promoting factors have been extensively 
studied for the past two decades. The growth inhibi- 
tors, however, have come to the attention of biolo- 
gists only recently. Yet they include some of the 
most widespread and versatile regulators of cell be- 
havior. Investigator Joan Massague, Ph.D. (Memorial 
Sloan-Kettering Cancer Center) and his colleagues 
have identified the proteins that act as the cell mem- 
brane receptors for a well-known inhibitor, trans- 
forming growth factor-/? (TGF-/3). Their study 
should lead to progress in elucidating the nature of 
the signals that instruct cells to stop proliferation, 
and may show ways to constrain the unrestricted 
growth of cancer cells. 
Investigator Steven L. McKnight, Ph.D. (Carnegie 
Institution) and his colleagues have studied mam- 
malian transcription factors. Cultured 3T3-L1 cells 
can be converted from mitotically proliferative fi- 
broblasts into terminally differentiated adipocytes 
in response to a discrete set of adipogenic hor- 
mones. The early phase of differentiation is marked 
by acute cell proliferation, whereas the late phase is 
marked by growth arrest and morphological special- 
ization. A family of transcription factors related to 
CCAAT/enhancer-binding protein (C/EBP) have 
been inferred to regulate the process of adipo- 
cyte differentiation. Two C/EBP-related proteins, 
C/EBP/3 and C/EBP6, are induced during the early 
proliferative phase of the differentiation program in 
response to two adipogenic hormones. A third pro- 
tein, C/EBPa, is expressed late during differentia- 
tion when cell growth is arrested and the special- 
ized, adipogenic phenotype is manifested. Ectopic 
expression of C/EBPa in otherwise proliferative 
cells causes growth arrest. The sequential activities 
of the three C/EBP proteins are believed to provide 
important cues along the differentiation pathway. 
Associate Investigator J. Evan Sadler, M.D., Ph.D. 
(Washington University) and his colleagues investi- 
gate the regulation of blood coagulation and, partic- 
ularly, the role of cells in this process. Cells in con- 
tact with the blood actively maintain a balance 
between stimulating and inhibiting blood coagula- 
tion. This balance is disrupted during inflammatory 
processes that are associated with bleeding or throm- 
bosis, such as bacterial infections, and in certain in- 
herited diseases. This laboratory has studied several 
endothelial cell hemostatic proteins, including von 
Willebrand factor and thrombomodulin, as well as 
the interaction of thrombomodulin with the blood- 
clotting enzyme thrombin. Mutations in the von 
Willebrand factor gene were characterized in pa- 
tients with von Willebrand disease, the most com- 
mon human, inherited, bleeding disorder. The 
regulation and structure-function relationships of 
thrombomodulin and of thrombin were investigated 
by mutagenesis and characterization of recombinant 
proteins. 
When blood clots form to block blood vessels 
(thrombosis), the process results in death to the 
surrounding tissue unless the clot can be broken up 
(lysed) rapidly. Investigator Charles T. Esmon, 
Ph.D. (Oklahoma Medical Research Foundation) 
and his colleagues developed a model for deep vein 
thrombosis and implicated inflammation as a major 
contributor to blood clot formation. This model can 
be used to test therapeutic approaches and to under- 
stand the relationship between thrombosis and in- 
flammation. A key to preventing clot formation is to 
inhibit the enzyme thrombin. Studies performed in 
the past year have identified some aspects of how 
thrombin clot-promoting activity is blocked by 
thrombomodulin, the protein that interacts with 
thrombin to activate protein C. These studies may 
contribute to the design of new clot-preventing 
drugs. 
TNF (tumor necrosis factor) is a protein hormone 
that is of particular importance in the development 
of shock and tissue injury during the course of in- 
fectious diseases. Associate Investigator Bruce A. 
Beutler, M.D. (University of Texas Southwestern 
Medical Center at Dallas) and his colleagues have 
shown that TNF is also constitutively produced 
within the thymus and placenta of normal animals. 
Using transgenic mice bearing markers of TNF syn- 
thesis and recombinant inhibitors of TNF activity, 
they are probing the regulation and function of this 
protein in order to understand its essential actions. 
The laboratory of Associate Investigator Donald E. 
Ganem, M.D. (University of California, San Fran- 
cisco) studies how viral pathogens replicate in their 
host cells and cause disease. Particular attention is 
paid to the hepatitis B viruses (HBVs), which pro- 
duce acute and chronic liver injury and predispose 
infected hosts to the development of liver cancer. 
Work is focused in two main areas: the molecular 
mechanisms by which these viruses replicate and 
the processes by which viral infection leads to 
cancer. Studies of viral replication have revealed 
that HBVs, like retroviruses, employ reverse tran- 
scription to replicate their DNA, and the details of 
how this occurs are being examined. This work may 
allow the identification of new targets for antiviral 
therapy. An experimental animal model is used to 
explore the development of liver cancer. Cellular 
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