Genes Responsive to Growth Factors 
Vikas P. Sukhatme, M.D., Ph.D. — Assistant Investigator 
Dr. Sukhatme is also Associate Professor of Medicine and Molecular Genetics and Cell Biology at the Uni- 
versity of Chicago. He received his Ph.D. degree in theoretical physics from the Massachusetts Institute of 
Technology. He then received his M.D. degree from Harvard Medical School. After residency and clinical 
fellowship training at the Massachusetts General Hospital, Boston, he completed his postdoctoral work at 
Stanford University. 
THE primary focus of our research is to under- 
stand the molecular events involved in the 
regulation of mammalian cell growth. Since cells 
grow in response to the presence of extracellular 
mitogens (growth factors) , we are attempting to 
define the mechanisms by which growth factors 
function. A complex series of events follows mi- 
togen-receptor binding, including the rapid gen- 
eration of second messenger signals in the cell's 
cytosol and plasma membrane. In turn, these 
events lead to the activation of a set of "immedi- 
ate-early" genes. 
During the past few years, work from our own 
and other laboratories has shown that an impor- 
tant subset of these genes encodes transcriptional 
factors — proteins that activate or repress another 
set of genes. Furthermore, upon mitogenic stimu- 
lation these genes are inducible in a wide variety 
of mammalian cells, suggesting that they are part 
of a general program involved in cell growth. 
More importantly, by virtue of their structure and 
induction kinetics, they are likely to play broad 
roles as "third messengers," by coupling early 
biochemical processes to long-term changes in 
gene expression required to modulate not only 
cell growth but other cellular processes such as 
differentiation. Therefore, our long-term goal is 
to understand how these proteins function as nu- 
clear signal transducers. 
To date, our laboratory has identified four early 
growth response (EGR) genes (EGRl-4). Each 
encodes a protein with three Cys2-His2 zinc finger 
motifs, structures previously described in other 
transcriptional regulatory proteins. The pre- 
dicted finger domains are nearly identical to each 
other and are closely related to that of another 
protein that may play a critical role in the genesis 
of a childhood kidney tumor (Wilms' tumor). 
These proteins function as transcription factors 
and bind to similar target sequences. Thus they 
can interfere with each other's ability to activate 
a test target gene. However, the physiologically 
important target gene(s) for the EGR proteins in 
the context of cell growth remains to be 
identified. 
We are currently attempting to define a func- 
tional role for the EGRl transcription factor in 
myeloid differentiation and in tumorigenesis. 
The human EGRl gene located on chromosome 5 
band q31 is deleted in the blast cells of many 
patients with therapy-related acute myeloid leu- 
kemia. These patients succumb to this disease 
after successful treatment of their primary malig- 
nancy years earlier. Recent fine-mapping data 
continue to support the hypothesis that EGRl is 
located in the critical region of chromosome 
5q31, the smallest common deleted region in 
these patients. If these data continue to hold up 
as the critical region is further refined, we will 
use pulse-field electrophoresis and blotting as 
well as polymerase chain reaction methodology 
and DNA sequencing to investigate the structure 
of the cytogenetically normal EGRl allele. To- 
ward this end, we have recently cloned and se- 
quenced the human EGRl cDNA. The overall hy- 
pothesis under consideration is that, like the 
retinoblastoma gene, the p53 gene, and the 
Wilms' tumor gene, EGRl might be a negative 
regulator of cell growth, at least in the context of 
myelopoiesis. 
Another emerging focus of our laboratory is the 
isolation of genes for transcription factors in- 
volved in the development of a solid organ, the 
kidney. Using oligonucleotide probes derived 
from conserved regions of zinc finger proteins, 
we have identified several clones expressed at 
high levels in the kidney. Molecular characteriza- 
tion of these clones and their expression patterns 
during development are in progress. As an alter- 
native approach, we are also attempting to charac- 
terize the genetic elements responsible for ex- 
pression of the Tamm-Horsfall protein. This 
glycoprotein is produced in all mammalian spe- 
cies, in a developmentally regulated and 
nephron-specific manner, and should serve as a 
useful starting point for defining aspects of kid- 
ney transcription and development. 
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