Control of Transcription 
by Transmembrane Signals 
Edward B. Ziff, Ph.D. — Investigator 
Dr. Ziff is also Professor of Biochemistry at the New York University Medical Center. He received his B.A. 
degree in chemistry from Columbia University and the Ph.D. degree in biochemistry from Princeton Uni- 
versity. He then studied DNA structure with Fred Sanger at the MRC Laboratory of Molecular Biology in 
Cambridge. He later conducted research on DNA tumor viruses at the Imperial Cancer Research Fund 
Laboratory, London, and in the Department of Molecular Cell Biology at the Rockefeller University. He 
later joined the New York University Medical Center and began the study of cellular mechanisms that 
control proliferation and differentiation. 
THE remarkable process of development re- 
quires that a fertilized egg undergo many 
rounds of cell division with accompanying differ- 
entiation to generate specialized cell types that 
ultimately form the mature organism. For devel- 
opment to proceed normally, just the right num- 
ber and types of cells must be available at each 
stage. It follows that any cell's decision to divide 
and/or differentiate must be carefully regulated. 
These two critical processes, proliferation and 
differentiation, are also controlled in the adult — 
for example, during the maintenance of tissues 
and in wound healing. 
The decision of a cell to divide or to express a 
specialized function is often determined by sig- 
nals from its environment. Prominent among the 
agents that convey such signals are the growth 
factors, which are polypeptides synthesized and 
secreted by cells. Our laboratory studies the mo- 
lecular mechanisms by which growth factors and 
other transmembrane signaling agents exert their 
effects on cell proliferation and differentiation. 
The transforming genes of DNA tumor viruses 
such as adenovirus often modify these programs 
and are therefore useful for dissecting the growth 
regulatory pathways. 
Growth factors transmit signals to cells by bind- 
ing to specific receptor proteins, which span the 
cell's plasma membrane and induce second mes- 
senger signals in the cytoplasm. The latter signals 
have a multitude of targets, some in the cyto- 
plasm and some in the nucleus. Although individ- 
ual growth factors may exert profound changes 
on cells, some effects, such as the induction of 
cell proliferation, may require the combined ac- 
tions of more than one growth factor. When the 
signal pathways are inappropriately activated, 
cells may lose control of growth and a tumor may 
arise. When the pathways are blocked, essential 
cell types may degenerate and die. It follows that 
errors in signaling can result in diverse sorts of 
diseases. 
In the case of the nervous system, transmem- 
brane signals induced by neurotransmitters regu- 
late the properties of neurons. These small mole- 
cules, released by neurons at synapses, bind to 
receptors on postsynaptic target cells. Neuro- 
transmitter stimulation of target neurons is a criti- 
cal step in the rapid transmission of nerve im- 
pulses, but it can also more slowly regulate the 
activities of specific genes, allowing the nervous 
system to modify its properties in response to its 
environment. Such modification may underlie 
the processes of neural adaptation and memory. 
Our laboratory has identified a group of imme- 
diate early-response genes that are rapidly in- 
duced by growth factor stimulation and appear to 
be primary targets in the nucleus for the growth 
factor-induced signals. Our work focuses on the 
c-fos gene, which is very rapidly induced by a 
wide range of transmembrane signals. This gene 
encodes a protein, c-Fos, which is a member of a 
family of transcription factors that bind to spe- 
cific sites in the regulatory regions of other genes 
and thereby control their activity. In this manner 
c-Fos acts as an intermediary for the conversion of 
short-term transmembrane signals into longer- 
term changes in the cell. 
We have shown that a protein kinase, Raf, 
which phosphorylates proteins on serine and 
threonine residues and which resides primarily in 
the cytoplasm, has a role in transmitting these 
activating signals to the c-fos promoter in the nu- 
cleus. Mutations that deregulate Raf can induce 
human tumors, and our work suggests that this 
may follow from aberrant activation of the ex- 
pression of early response genes such as c-fos. 
We have also identified novel transcription fac- 
tor proteins that bind to regulatory regions of the 
c-fos promoter and activate the gene in response 
to second messenger signals. One factor is re- 
sponsive to cAMP and moves from the cytoplasm 
to the nucleus upon activation. It apparently co- 
operates with other factors to enable a wide range 
of transmembrane signals to activate the gene. 
We are particularly concerned with the role of 
c-fos in programs of neuronal differentiation in- 
duced by nerve growth factor (NGF). In vivo, 
NGF is required for the differentiation and main- 
tenance of peripheral neurons. Expression of 
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