fibrinolysis, tissue remodeling, and metastasis; 2) 
the hemagglutinin of influenza virus, which is being 
used to develop models of autoimmune disease in 
transgenic mice; and 3) the tumor-suppressor pro- 
tein p53 and its interaction with cytosolic stress-70 
proteins. Basic studies on the cellular role and regu- 
lation of protein chaperones are also under study. 
The research group headed by Investigator Lewis 
T. Williams, M.D., Ph.D. (University of California, 
" San Francisco) has shown a connection between two 
molecules, phosphatidylinositol 3-kinase and p21 
ras, that are known to regulate cell growth. They 
were surprised to find that a set of reactions previ- 
ously thought to be important for the action of sev- 
eral growth factors are not required for at least one 
of these factors to stimulate cell proliferation. They 
also found that a regulatory molecule, Raf-1, plays 
an essential role in vertebrate embryonic develop- 
ment. Finally, they cloned the gene for a new recep- 
tor that is important for the growth of blood vessels. 
Work in the laboratory of Associate Investigator 
Gerald R. Crabtree, M.D. (Stanford University) is di- 
rected at understanding how cells achieve their final 
identity. Beginning with the same genetic informa- 
tion, cellular decisions are made whereby some be- 
come blood cells, others brain cells, and so forth. 
However, the basis of these decisions is only re- 
cently becoming understood. One specific area of 
work in the laboratory involves the T lymphocytes 
of the immune system that coordinate the activity of 
other cells to mount an immune response to an in- 
vading organism or transplanted tissue. The drug 
most commonly used to suppress the rejection of a 
transplant, cyclosporin A, works by interfering with 
the ability of a T cell to differentiate into an immuno- 
logically functional cell. Work in the Crabtree labo- 
ratory and in Dr. Stuart Schreiber's laboratory in Bos- 
ton has led to a precise understanding of how these 
drugs function and has opened new avenues for the 
development of more-specific immunosuppressive 
agents. 
The focus of the research of Assistant Investigator 
Rudolf Grosschedl, Ph.D. (University of California, 
San Francisco) and his colleagues is the develop- 
mental control of gene expression. In particular, 
gene transfer of wild-type and mutated immunoglob- 
ulin /X heavy-chain genes into the mouse germline 
has indicated that negative regulation of enhancer 
function is important for tissue-specific gene ex- 
pression. Moreover, the ^ enhancer is capable of al- 
tering the accessibility of nuclear factor-binding 
sites in native chromatin, independent of transcrip- 
tion. With the goal of identifying and characterizing 
cell lineage-specific regulators of transcription, the 
group isolated cDNA clones encoding two novel 
lymphocyte-specific factors. Lymphoid enhancer- 
binding factor 1 (LEF- 1 ) is a member of the family of 
the high-mobility group (HMG) of proteins and par- 
ticipates in the regulation of the T cell receptor a 
gene enhancer. In binding to DNA, LEF-1 recognizes 
its target site through contacts in the minor groove 
in the DNA helix and induces a very sharp bend. 
Another lineage-specific protein, early B cell factor 
(EBF), binds a functionally important site in the 
promoter of the mb-l gene, which is expressed spe- 
cifically at early stages of B cell difi'erentiation. EBF 
was purified, and cDNA clones encoding this pro- 
tein were isolated. The roles of LEF-1 and EBF for 
lineage-specific gene expression and cell difi'eren- 
tiation are under study. 
In the laboratory of Investigator Nathaniel Heintz, 
Ph.D. (Rockefeller University), high-resolution ge- 
netic mapping studies have resulted in the identifi- 
cation of molecular markers in close proximity to 
genes involved in a specific developmental defect 
of the mammalian central nervous system and in two 
neurodegenerative diseases of mice. Efforts to iden- 
tify a series of tissue-specific, developmentally regu- 
lated genes expressed in the mammalian cerebel- 
lum have resulted in the cloning of a variety of genes 
whose expression marks important biological tran- 
sitions in the mammalian central nervous system 
and should provide insight into important molecu- 
lar events controlling development of the mamma- 
lian brain. Studies of transcription factor phosphor- 
ylation during the cell cycle have been extended to 
establish that similar mechanisms regulate distinct 
histone gene transcription factors (Oct-1, H1TF2). 
These results imply that a common program of post- 
translational modifications may regulate S-phase- 
specific transcription and, perhaps, DNA replica- 
tion, during the mammalian cell cycle. 
Assistant Investigator Richard L. Maas, M.D., Ph.D. 
(Brigham and Women's Hospital) and his colleagues 
are investigating the role that certain genes play in 
the embryonic development of the mammalian eye 
and kidney. The genes of primary interest contain 
either of two DNA-binding functions, a paired box 
or a homeobox, and are therefore likely to be in- 
volved in regulating the activity of other genes that 
actually carry out the steps involved in forming 
various organs. The PAX6 gene has been identified 
as being very important in the formation of the hu- 
man eye. Mutations in it are responsible for aniridia, 
a disorder of eye development frequently culminat- 
ing in blindness. Studies are under way to determine 
how PAX6 functions. In addition, certain steps of 
kidney development are under study, and the gene 
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