model for type I diabetes; 2) human tissue-type 
plasminogen activator, which is being studied by 
oligonucleotide-directed mutagenesis to analyze 
the structure-function relationships of the individ- 
ual domains of the molecule; and 3) BiP, a luminal 
protein of the endoplasmic reticulum that appears 
to be involved in the initial mobilization of proteins 
that traverse the secretory pathway. 
Assistant Investigator Leland Ellis, Ph.D. (Univer- 
=^-sity of Texas Southwestern Medical Center at Dal- 
las) and his colleagues are interested in the struc- 
ture and function of those components of the 
plasma membrane that initiate the response of cells 
to extracellular stimuli, especially cell surface re- 
ceptors. The insulin receptor comprises two large, 
soluble, functional domains connected by a single 
membrane-spanning domain. The two domains act 
in concert upon ligand binding (transmembrane 
signaling) to initiate the insulin response in cells, 
but each is also capable of autonomous function 
(ligand binding and protein tyrosine kinase activity, 
respectively). In collaborative studies with Dr. Rob- 
ert E. Hammer (HHMI, University of Texas South- 
western Medical Center at Dallas), transgenic mice 
that express wild-type or altered forms of the re- 
ceptor are being utilized to explore insulin recep- 
tor structure and function in the context of the in- 
tact animal, while the expression of soluble 
derivatives of each of the two major functional do- 
mains of the receptor facilitates the analysis of their 
biochemical and biophysical properties. Biochemi- 
cal, molecular genetic, and transgenic approaches 
are also being employed to identify and study 
growth cone membrane-associated proteins in an 
effort to understand how growing nerve cells ex- 
plore and respond to the complex extracellular mi- 
croenvironment encountered during development 
of the nervous system. 
Gene expression in animal cells is a complex 
process involving multiple, distinct steps. Expres- 
sion of individual genes can be controlled at one or 
more of these steps, including messenger RNA syn- 
thesis, RNA processing, RNA transport, RNA half- 
life, protein synthesis, and protein half-life. The lab- 
oratory of Investigator Thomas Shenk, Ph.D. 
(Princeton University) uses a human DNA tumor 
virus, adenovirus, as a model to study the control 
of gene expression in animal cells. During the past 
year his laboratory has focused on the identification 
and characterization of cellular factors that mediate 
and regulate the synthesis of adenovirus mRNAs. 
Transcriptional regulation in eukaryotic cells is 
primarily mediated through protein: DNA com- 
plexes. These complexes can form on DNA either 
close to the promoters for specific genes or at very 
distant sites, termed enhancers. In either case, the 
underlying DNA sequence encodes an ordered se- 
ries of recognition sites for sequence-specific DNA- 
binding proteins. The appropriate amalgamation of 
binding sites somehow dictates when and where a 
gene is to be transcribed. Investigator Steven L. 
McKnight, Ph.D. (The Carnegie Institution of Wash- 
ington) and his colleagues have used molecular ge- 
netic techniques to define the minimal DNA se- 
quence elements from which enhancers and 
promoters are built and have used biochemical 
techniques to purify and study proteins that recog- 
nize these sequence elements. 
The laboratory of Associate Investigator Nathan- 
iel Heintz, Ph.D. (The Rockefeller University) is also 
interested in understanding the molecular events 
that lead to the expression of specific genes at par- 
ticular times during the growth of mammalian cells. 
Efforts during the past year have resulted in the 
identification of several molecules that participate 
directly in the regulation of histone genes, whose 
activation occurs at a specific time during the cell 
growth cycle. Characterization of these molecules 
has led to the realization that a common mecha- 
nism may exist for activation of all macromolecular 
synthesis during the S phase of the cell cycle. Eluci- 
dation of this common mechanism may lead to 
some fundamental insight into the regulation of 
cell growth. Dr. Heintz's laboratory has also initi- 
ated a variety of approaches toward isolating genes 
that are involved in the development of the mam- 
malian cerebellum. 
Associate Investigator Elaine Fuchs, Ph.D. (The 
University of Chicago) and her colleagues seek to 
understand the molecular mechanisms that under- 
lie growth, differentiation, and development in 
human epithelia, primarily the epidermis and its 
appendages. In the past year they have introduced 
a human keratin gene into mice and showed that it 
is properly regulated in skin cells. This approach is 
an important step in specifically targeting genes to 
skin. A second accomplishment was the demonstra- 
tion that vitamin A inhibits abnormal differentiation 
in squamous cell carcinoma cells. Although this in- 
hibition is encouraging, retinoids also increase pro- 
liferation of epidermal cultures, a potentially seri- 
ous side effect for long-term retinoid treatments of 
various skin diseases. The laboratory also has engi- 
neered mutations in keratins and showed that they 
have a dominant effect when made by epidermal 
cells in culture. This suggests that naturally occur- 
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