ally, suggesting that these two pairs of residues may 
form a salt bridge in the three-dimensional structure 
of the permease. Therefore it is possible that the 
region of the protein thought to be helix VII, which 
contains two of these charged residues (aspartic 
acid), may be in close proximity to the regions 
thought to be helices X and XI, which contain the 
other two interacting residues (lysine) . 
Associate Investigator Linda J. Pike, Ph.D. (Wash- 
ington University) and her colleagues are interested 
in the mechanism of action of growth factors. They 
have shown that the activity of an intracellular en- 
zyme, a phosphatidylinositol kinase, is stimulated in 
response to epidermal growth factor (EGF). This 
enzyme has been purified and cloned using recombi- 
nant DNA technology. Other studies have shown 
that prolonged treatment of cells with EGF renders 
them insensitive to further stimulation by that 
growth factor, a phenomenon termed desensitiza- 
tion. The cell surface receptor for EGF is a single 
polypeptide chain. Upon binding of EGF, two poly- 
peptide chains associate to form a receptor dimer 
and mediate the biological effects of the hormone. 
In desensitized cells, EGF receptor dimer formation 
is blocked, explaining the inability of the cells to 
respond to the growth factor. The protein kinase 
p34cdc2 j^gg been shown to phosphorylate the EGF 
receptor and may be responsible for inducing re- 
ceptor desensitization. 
The laboratory of Assistant Investigator Roger J. 
Davis, Ph.D. (University of Massachusetts) is fo- 
cused on the investigation of the molecular basis of 
the interaction of cell surface receptors with poly- 
peptide growth factors. In the past year the labora- 
tory has investigated the role of the phosphorylation 
of a serine residue located within the carboxyl- 
terminal domain of the EGF receptor. Phosphoryla- 
tion at this site was found to account for the process 
of homologous desensitization of the receptor. Mu- 
tations at this negative regulatory site blocked de- 
sensitization and resulted in the formation of tumors 
in animals. In other research, a family of human 
protein-serine/threonine kinases that are regulated 
by EGF were molecularly cloned and characterized. 
These protein kinases were shown to translocate 
into the nucleus of EGF-treated cells and to activate 
the transcription factor c-Myc. These findings estab- 
lish a pathway of signal transduction from a cell sur- 
face receptor to the regulation of gene expression in 
the nucleus. 
Associate Investigator Nancy L. Craig, Ph.D. 
(Johns Hopkins University) and her colleagues are 
dissecting the transposition mechanism of the bacte- 
rial transposon Tn7, focusing on defining the macro- 
molecular interactions and the DNA strand cleavage 
and joining reactions that mediate this reaction. 
They are using both genetic and biochemical meth- 
ods to probe their hypothesis that TnsB, a sequence- 
specific DNA-binding protein that interacts with the 
Tn7 ends, contains the catalytic sites for recombina- 
tion. They are looking for "gain-of-function" TnsB 
mutants that will reveal these activities and are also 
examining the ability of TnsB and other Tn7 recom- 
bination proteins to react with novel DNA substrates 
that mimic transposition intermediates. 
Cystic fibrosis is a common genetic disease 
caused by mutations in the gene encoding the cystic 
fibrosis transmembrane conductance regulator 
(CFTR). Investigator Michael J. Welsh, M.D. (Uni- 
versity of Iowa) and his colleagues have shown that 
CFTR is a chloride channel that is involved in the 
secretion of chloride ions by the cells affected by 
cystic fibrosis. Their work has demonstrated that the 
opening and closing of this channel is controlled in 
novel ways by second messengers within the cells. 
The group is also studying the mechanisms that 
cause defective function of CFTR. The results of 
these studies should yield new insights into the nor- 
mal biology of CFTR and contribute to knowledge of 
how mutations in the gene encoding this protein 
cause disease. 
The goal of the research in the laboratory of Assis- 
tant Investigator James M. Wilson, M.D., Ph.D. (Uni- 
versity of Michigan) is to enhance an understanding 
of inherited diseases and to develop new treatments 
based on gene replacement. One disorder under in- 
vestigation, familial hypercholesterolemia (FH), is 
caused by a defect in a liver-specific gene responsi- 
ble for clearing cholesterol from the blood. These 
patients have severe elevations in blood cholesterol 
and suffer from coronary artery disease in child- 
hood. Using a rabbit animal model for FH, Dr. Wil- 
son and his colleagues have developed a new ap- 
proach to treatment that is based on correcting the 
genetic defect in the patient's own liver cells, which 
has led to a clinical trial. The other disease under 
investigation in this laboratory is cystic fibrosis 
(CF). This inherited disorder causes pathology pri- 
marily in the lung and pancreas. The group is at- 
tempting to identify the abnormalities that lead to 
lung disease. They are also developing approaches 
to therapy based on inhalation of a recombinant 
virus that carries a normal functioning CF gene. 
The overall aim of the research of Investigator 
Elaine Fuchs, Ph.D. (University of Chicago) and her 
colleagues is to understand the molecular mecha- 
nisms that underlie growth, differentiation, and de- 
velopment in the human epidermis of the skin. In 
the past year, this laboratory has I) identified the 
genetic bases for two human skin diseases, epider- 
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