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. He completed an internship and residency in medicine at Columbia- 
Presbyterian Medical Center, New York. His postdoctoral research was done at the National Cancer Insti- 
tute and the Rockefeller University. Dr. Nathans is a member of the National Academy of Sciences. He 
received the Nobel Prize in medicine or physiology in 1978. 
THE growth of mammalian cells is regulated 
by extracellular proteins called growth fac- 
tors. How these proteins induce cell growth is a 
key question relevant not only to the regulation 
of cell proliferation and tumorigenesis but more 
generally to the response of cells to a variety of 
extracellular signaling agents, such as develop- 
mental factors, classical hormones, cell surface 
and matrix proteins, and neurotransmitters. 
The first step in the stimulation of cell growth 
by a growth factor is the interaction of the factor 
with a specific cell-surface receptor. This inter- 
action rapidly induces a cascade of biochemical 
reactions in the cell, leading to the sequential 
activation of specific cellular genes and subse- 
quent DNA replication and cell division. The or- 
dered expression of cellular genes induced by 
growth factors has the attributes of a regulated 
genetic program. Research in my laboratory con- 
cerns the analysis of this program and its role in 
cell proliferation. 
To identify some of the genes activated by 
growth factors we used recombinant DNA meth- 
ods to isolate DNA copies (cDNAs) of gene mes- 
sages present in cultured fibroblastic mouse cells 
only after they have been stimulated by a growth 
factor or by serum that is rich in a growth factor 
derived from blood platelets. We and others have 
identified one set of genes, the immediate-early 
genes, which are activated within 2 or 3 minutes 
after addition of growth factor, coordinately with 
activation of the proto-oncogenes fos or myc de- 
tected previously. Some of these immediate-early 
genes encode proteins related to known tran- 
scription factors (proteins that regulate gene ex- 
pression), others encode secreted proteins or 
membrane proteins, and others encode proteins 
that are part of the filamentous structures of cells. 
We have concentrated largely on genes that en- 
code probable transcription factors, because 
these are likely to be involved in regulating the 
genetic program induced by growth factors. 
We previously described immediate-early tran- 
scription factors with "zinc finger" motifs and 
others that are "leucine zipper" proteins of the 
Jun family. During the past year we have identi- 
fied three additional immediate-early proteins 
whose structures are related to those of known 
transcription factors. One of the proteins is 
Nup475, a nuclear, zinc-binding protein that has 
two copies of a sequence that suggests it can form 
a novel type of zinc finger. Studies are under way 
to determine if Nup475 binds to a specific DNA 
sequence and regulates transcription. 
The second protein, AFosB, is a naturally occur- 
ring shortened form of FosB, a previously de- 
scribed member of the Fos proto-oncogene fam- 
ily of transcription factors. Expression of AFosB 
was found not only in growth factor-stimulated 
cultured cells but also in specific parts of the 
brain after electrical stimulation and in regener- 
ating liver. Like other members of the Fos family, 
AFosB can form dimers with members of the Jun 
family, and the dimers can bind to signals in DNA. 
However, unlike other Fos-Jun dimers, AFosB-Jun 
dimers are not transcriptionally active. Instead, 
AFosB competitively inhibits the transcriptional 
activities of Jun and Fos; it may therefore serve as 
a negative regulator of Jun and Fos during the 
growth response. 
The third protein is HLH462, which is related 
to the helix-loop-helix class of transcription regu- 
lators. Proteins of this class form dimers through 
their helix-loop-helix structural domains. Some 
dimers bind to signals in DNA, whereas others 
cannot bind to DNA because they lack a DNA- 
binding region. Helix-loop-helix proteins of the 
latter type have been shown to inhibit the tran- 
scriptional activity of DNA-binding helix-loop- 
helix proteins. HLH462 has the structural and 
functional properties of an inhibitory helix-loop- 
helix protein. It is expressed in many mouse tis- 
sues and in early mouse embryos. What role it 
plays in the growth factor-induced program is 
not yet clear. One possibility is that it inhibits a 
negative growth regulator present in nongrowing 
cells. 
So far, approximately 15 known or probable 
transcription factors have been identified among 
the immediate-early proteins induced in fibro- 
blasts by serum growth factors. Later in the cellu- 
lar response other genes are activated whose 
encoded proteins are thought to mediate progres- 
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