The Genomic Response to Growth Factors 
Daniel Nathans, M.D. — Senior Investigator 
Dr. Nathans is also University Professor of Molecular Biology and Genetics at the Johns Hopkins University 
School of Medicine. He received his B.S. degree in chemistry from the University of Delaware and his M.D. 
degree from Washington University. His postdoctoral research was done at the National Cancer Institute 
and the Rockefeller University. Dr. Nathans is a member of the National Academy of Sciences and serves 
on the President's Council of Advisers on Science and Technology. He received the Nobel Prize in medicine 
or physiology in 1978 for the application of restriction enzymes to problems in molecular genetics. 
THE proliferation of mammalian cells is regu- 
lated by extracellular proteins called growth 
factors. When a growth factor interacts with its 
specific cell surface receptor, a cascade of bio- 
chemical reactions leads to the sequential activa- 
tion of specific genes. Research in my laboratory 
concerns the analysis of this induced genetic pro- 
gram in a mouse fibroblast cell line. 
Among the genes expressed in the first wave of 
gene activation induced by growth factors are 
many that encode transcriptional regulatory pro- 
teins. We have previously described several of 
these "immediate-early" transcription factors, 
including members of the Jun and Fos families, 
zinc finger proteins, and a helix-loop-helix pro- 
tein. During the past year we have continued our 
characterization of these proteins and their 
genes. 
Several of the immediate-early transcription 
factor genes are activated by platelet-derived 
growth factor (PDGF) and other ligands through 
one or more serum response elements (SREs) up- 
stream of each gene. In the case of jun-B, the 
upstream sequence near the start of the gene has 
no functional SRE, nor other signals essential for 
activation of the gene. By analyzing a series of 
mutants, a graduate student in the laboratory, 
Evelio Perez-Albuerne, has found that jun-B has 
regulatory elements downstream of the gene, in- 
cluding a functional SRE and a cyclic AMP re- 
sponse element that mediates the activation of 
jun-B by agents that elevate intracellular cAMP. 
Thus the mechanism of activation of jun-B by 
serum or PDGF appears to be similar to that previ- 
ously found for a number of other immediate- 
early genes, except that the response elements 
are farther away from the start of transcription 
and downstream of the gene. 
The Jun and Fos family of proteins are DNA- 
binding transcription factors that form dimers 
through interacting domains called leucine zip- 
pers. Pierre Chevray, another graduate student, 
has initiated a search for other proteins that inter- 
act with Jun and Fos and regulate their activities. 
For this purpose he used a previously described 
yeast genetic system that allows one to detect 
protein-protein interactions and to clone the 
gene for an interacting protein. By this means he 
has identified several proteins that interact with 
the Jun segment that forms a leucine zipper. 
Among these proteins are another leucine zipper 
transcription factor, two previously unidentified 
proteins, and the cytoskeletal proteins a- and 
/3-tropomyosin, which are known to form leucine 
zippers. We are now exploring the physiological 
significance of these interactions. 
After the appearance of immediate-early tran- 
scription factors in growth factor-treated cells, 
another set of genes comes into play. Activation 
of these "delayed-early" genes is thought to be 
mediated by immediate-early transcription fac- 
tors. Associates Anthony Lanahan and John 
Williams have cloned and characterized a num- 
ber of cDNAs corresponding to delayed-early 
genes. Some of the genes are induced by mitogens 
in nonfibroblastic cell lines also. Among the pro- 
teins they encode are a chromosomal protein, a 
transmembrane channel protein, an enzyme in- 
volved in adenine nucleotide biosynthesis, a pro- 
tein related to a known cytokine, and several pre- 
viously unidentified proteins. We are further 
characterizing some of these. In addition, we are 
studying the role of immediate-early transcrip- 
tion factors in activating their genes. 
Research on the Jun proteins is supported by a 
grant from the National Institutes of Health. 
289 
