Articles 
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GENOMIC RESPONSE TO GROWTH FACTORS 
Daniel Nathans, M.D., Senior Investigator 
Proliferation of mammalian cells is regulated by 
polypeptide growth factors. Growth factors act via 
specific cell surface receptors and intracellular mes- 
senger systems to induce genetic programs in target 
cells. Research in the laboratory of Dr. Nathans has 
been aimed at characterizing the genetic program 
induced in cultured fibroblasts by serum growth 
factors. 
When nonproliferating mouse 3T3 cells are stimu- 
lated with serum or platelet-derived growth factor 
(PDGF), sets of genes are activated sequentially. 
The first set of genes, called immediate-early genes, 
is activated within minutes after the cells are stimu- 
lated. They include genes that encode a variety of 
transcription factors, among them leucine zipper 
proteins (Fos and Jun family members) , zinc finger 
proteins (Zif268 and related proteins and Nur77), 
and helix-loop-helix proteins (Myc, HLH462). An- 
other set of genes, called delayed-early genes, is ex- 
pressed within a few hours after cells are stimulated. 
Expression of delayed-early genes requires new 
protein synthesis, presumably the synthesis of 
immediate-early transcription factors responsible 
for activating delayed-early genes. During the past 
year studies have focused on selected immediate- 
early transcription factor genes and on systematic 
identification of delayed-early genes and their possi- 
ble regulatory sequences. 
Activation of jun-B 
Several immediate-early genes are activated by 
serum or PDGF through one or more serum response 
elements (SREs) upstream of each gene. In the case 
of jun-B, the upstream sequence near the start of the 
gene has no SRE, nor is an upstream segment linked 
to CAT sufficient for response to activation by 
growth factors. By assaying a series of mutant Jun-B 
genes for transcriptional activation by serum or 
PDGF, Evelio Perez-Albuerne (a graduate student in 
Dr. Nathans' laboratory, whose research is sup- 
ported by the National Cancer Institute) has found a 
regulatory region immediately downstream of jun- 
B. Within the regulatory region is a typical SRE and a 
cAMP response element (CRE). Nucleotide substi- 
tutions within the SRE reduce responsiveness of 
jun-B to serum, PDGF, and fibroblast growth factor 
(FGF) . Nucleotide substitutions within the CRE re- 
duce responsiveness to forskolin. Thus the mecha- 
nism of activation of jun-Bhy serum, PDGF, or FGF 
appears to be similar to that found for a number of 
other immediate-early genes, except that the re- 
sponse element is farther away from the start of tran- 
scription and is downstream of the gene. 
Proteins That Interact with Jun and Fos 
Jun and Fos family members are sequence- 
specific, DNA-binding transcription factors. To bind 
GENETICS 233 
