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TRANSCRIPTION FACTORS IN CELL GROWTH AND KIDNEY DIFFERENTIATION 
VntAsP. SuKHATME, M.D., Ph.D., Assistant Investigator 
The focus of Dr. Sukhatme's laboratory is on clon- 
ing mammalian transcription factor genes that func- 
tion in two dilferent contexts. The first relates to 
regulatory genes whose induction is modulated dur- 
ing the transition of quiescent cells into the Gi 
phase of the cell cycle. These immediate-early tran- 
scription factor genes are also induced by diverse 
extracellular signals. A second set of studies is aimed 
at characterizing transcription factor cascades of im- 
port during kidney differentiation. These two proj- 
ects have recently intersected in studies with the 
Wilms' tumor gene WTl. 
EGR Family of Immediate-Early 
Transcription Factors 
Extracellular signals such as neurotransmitters, 
growth factors, hormones, and matrix are known to 
be key modulators of cellular phenotype. These 
agents lead to the generation of second messenger 
signals in the plasma membrane and cytosol. In turn, 
these biochemical events modulate the expression 
of a set of so-called immediate-early genes (lEGs), 
whose induction does not require de novo protein 
synthesis. Several years ago, Dr. Sukhatme's labora- 
tory and others identified several lEGs primarily in 
the context of a mitogenic response and more specif- 
ically in the transition of a cell out of a quiescent 
state (Go) into Gj. Of particular interest to Dr. 
Sukhatme's laboratory has been a subset of lEGs that 
encode transcription factors, since as such they 
might 1) be the targets for second messenger events 
and 2) activate or repress the transcription of criti- 
cal genes required to effect a particular cellular 
phenotype. 
In 1987 Dr. Sukhatme's laboratory discovered 
(concurrently with several other laboratories) the 
EGR family of lEGs. The best-characterized of these 
genes is Egr-1 (early growth response gene-1). 
Egr-1 (also known as Zif-268, Tis-8, NGEI-A, and 
Krox-24) was isolated as a serum-inducible lEG in 
quiescent fibroblasts (Gq-G, transition), utilizing a 
differential screening protocol. The gene is induced 
by mitogenic stimulation in every mammalian cell 
type tested, including B cells; T cells; kidney mesan- 
gial, glomerular, and tubular epithelial cells; he- 
patocytes; and endothelial cells. The cDNA struc- 
ture predicts a protein whose carboxyl terminus 
contains three zinc fingers of the Cys2-His2 type, first 
identified in the Xenopus transcription factor 
TFIIIA. 
An exciting part of the Egr-1 story is that this 
gene, like c-fos and c-jun, can be activated in many 
physiologic contexts in addition to being ubiqui- 
tously induced in a mitogenic response. For exam- 
ple, during the past year it was discovered that ion- 
izing radiation can induce Egr-1 mRNA in certain 
cell types. Egr-1 is also an immediate-early gene in 
this context, and kinase C is critical in this induc- 
tion. The DNA sequences responsible for this stimu- 
lation include the CArG boxes — i.e., the multiple 
serum response elements present in the Egr-1 pro- 
moter (collaboration with Drs. Donald Kufe [Har- 
vard Medical School] and Ralph Weichselbaum [Uni- 
versity of Chicago]). These studies may define 
radiation-responsive cis sequences that could drive 
heterologous genes, thus leading to a novel modal- 
ity for "targeted" gene therapy, with activation con- 
trolled exogenously by ionizing radiation. 
Dr. Sukhatme and his colleagues have also been inter- 
ested in structure-function studies of the Egr- 1 protein. 
Does this protein function as a transcription factor via 
268 
