Transcription Factors in Cell Growth 
and Kidney Differentiation 
Vikas P. Sukhatme, M.D., Ph.D. — Assistant Investigator 
Dr. Sukhatme is also Associate Professor of Medicine and of Molecular Genetics and Cell Biology at the 
University 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. 
MY laboratory has been engaged in cloning 
and characterizing mammalian genes that 
code for transcription factors. One focus is on 
signal transduction, specifically on mitogenic sig- 
naling, and another aims at identifying transcrip- 
tion factors that control kidney development. 
These two interests have recently intersected, as 
delineated below. 
The Egr Family of Immediate-Early 
Transcription Factors 
Extracellular "signals" in the form of neuro- 
transmitters, growth factors, hormones, and ma- 
trix are known to control cellular phenotype. 
These agents lead to the generation of second 
messenger signals in the plasma membrane and 
cytosol. In turn, these biochemical events modu- 
late the expression of so-called immediate-early 
genes (lEGs) , whose induction does not require 
de novo protein synthesis. Several years ago, we 
and others identified several lEGs in the context 
of a mitogenic response, and more specifically in 
the transition of a cell out of a quiescent state 
(Go) into Gi . Of particular interest to us has been 
a subset of lEGs that encode transcription factors 
(proteins that bind DNA and regulate gene tran- 
scription), since they might couple short-term 
responses in the form of second messenger events 
to long-term changes in gene expression instru- 
mental in altering phenotype. 
The best characterized of these immediate- 
early transcription factor genes include members 
of the Fos family. c-Fos, identified as the cellular 
homologue of the \-Fos oncogene present in two 
viruses that cause osteosarcomas, was discovered 
in 1984 to be an lEG in serum-stimulated fibro- 
blasts. However, it was not until four years later 
that Fos was shown to be part of the AP- 1 tran- 
scription factor complex, composed of Fos-Jun 
heterodimers and other less well characterized 
proteins. c-Jun was likewise first identified as the 
cellular homologue of the \-Jun transforming 
gene. It was suspected to be a transcription factor 
through homology to part of the yeast GCN4 
protein. 
In 1 987 we discovered (concurrently with sev- 
eral other laboratories) the Egr family of lEGs. 
The best-characterized gene in this family is 
Egr-1 (early growth response gene-1). Egr-1 
(also known as Zif-268, Tis-8, NGFI-A, and 
Krox-24) was isolated as a serum-inducible lEG 
in quiescent fibroblasts (Gq-Gj transition), utiliz- 
ing a differential screening protocol. The gene is 
induced by mitogen stimulation in every mam- 
malian cell type tested, including B cells; T cells; 
kidney mesangial, glomerular, and tubular epi- 
thelial cells; hepatocytes; and vascular smooth 
muscle and endothelial cells. It is also induced by 
nerve growth factor in PCI 2 pheochromocytoma 
cells, a physiological context in which mitotic 
cells convert to a nonmitotic state. 
The cDNA structure predicts a protein whose 
carboxyl terminus contains three zinc fingers of 
the Cys2-HiS2 type, first identified in the Xenopus 
transcription factor TFIIIA. This prediction has 
recently been verified by Carl Pabo (HHMI, Mas- 
sachusetts Institute of Technology) and his col- 
leagues through analysis of the crystal structure 
of the zinc finger domain cocrystallized with its 
target DNA sequence GCGGGGGCG. 
We have been interested in identifying the 
events, from cell surface to nucleus, that modu- 
late Egr l expression. Although identification of 
such "upstream" or "proximal" events can ei- 
ther be attempted in the context of mitogenesis 
or in other situations in which Egr- 1 mRNA levels 
change, most of our work has been restricted to 
cell proliferation studies in fibroblasts. It has 
been found that multiple kinases regulate Egr- 1 
expression. For example, activation of the PDGF 
(platelet-derived growth factor) receptor or the 
EGF (epidermal growth factor) receptor by their 
cognate ligands leads to Egr-1 induction. 
v-Src has been shown to regulate Egr-1 inde- 
pendent of protein kinase C. More recently, we 
have found that v-Raf, a serine-threonine kinase, 
whose activation results from the convergence of 
diverse cell surface signals, leads to Egr-1 induc- 
tion. Furthermore, a dominant negative mutant of 
v-Raf will ablate the v-Src induction of Egr-1 , sug- 
gesting that v-Src stimulates Egr- 1 via v-Raf. Even 
if Egr-1 served as nothing more than a target 
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