Control of Transcription by Transmembrane Signals 
element and induces expression. This participa- 
tion of c-Fos in TH control may allow a neuron to 
coordinate the production of catecholamine neu- 
rotransmitters with the activity of the neuron 
during its function in the nervous system. Indeed, 
stimuli provided by light or smell may use this 
pathway to control neuronal activity. 
The c-Fos protein belongs to a family of pro- 
teins including FosB and Fral and Fra2, all of 
which may bind to c-Jun or to members of the Jun 
protein family. The resulting complexes in turn 
may all bind to the same DNA element. The dif- 
ferent c-Fos family members differ in their pat- 
terns of expression following cell stimulation, 
as well as in their structures outside the DNA- 
binding domain. This suggests that they may regu- 
late gene activity differentially when complexed 
with a DNA element such as the TH gene regula- 
tory element. 
Recent studies in our laboratory indicate that 
the TH gene is repressed by a mechanism in 
which the c-Fos protein, an activator, is replaced 
by a different c-Fos family member, which serves 
as a repressor. Indeed, other Fos family members, 
including FosB, become the predominant species 
as c-Fos levels dwindle and TH transcription is 
shut off. 
We have gone on to show that NGF induces 
other genes as well. One of these encodes periph- 
erin, a neuron-specific intermediate filament 
protein that is present in the axons of peripheral 
neurons as a component of the neuronal cytoskel- 
eton. Our studies of the developing rat nervous 
system indicate that peripherin expression coin- 
cides with the final steps of neuronal maturation 
and acquisition of function. 
The mechanisms that control peripherin ex- 
pression appear to be quite distinct from those 
that control c-Fos or TH. We detect no binding 
site for the Fos-Jun complex in the peripherin 
gene. Instead, a negative regulatory element ap- 
pears to release an inhibitory factor, thus activat- 
ing the gene. 
Study of these mechanisms may give a clue to 
how cells permanently exit from the cell cycle 
and induce the expression of genes that they em- 
ploy after losing the capacity to proliferate. One 
event that may block exit from the cell cycle is 
the loss of control of expression of c-myc, an- 
other growth factor-induced gene. It encodes a 
protein, c-Myc, that is distantly related to c-Fos 
and has specialized, but poorly understood, func- 
tion in inducing cell proliferation. It is expressed 
at abnormally high levels in many tumors. 
We have identified a DNA nucleotide sequence 
to which c-Myc can bind and a protein partner of 
c-Myc called Myn that can stimulate its DNA bind- 
ing. Our studies of c-Myc and Myn and their com- 
plexes with DNA indicate they are controlled at 
many levels, including modification of the ma- 
ture proteins by phosphorylation. Our studies 
seek to reveal the role of c-Myc in normal cell 
proliferation and in tumorigenesis. These studies 
are supported by the National Institutes of 
Health. 
We find that c-Myc expression is elevated in the 
naturally occurring childhood brain tumor me- 
dulloblastoma. The tumor cells have been 
blocked to differentiation and have proliferated 
abnormally. We also find that the transforming 
gene of adenovirus. El a, like c-myc, can block 
the differentiation of our model neurons, mimick- 
ing the state of the tumor. 
We are introducing various sorts of mutants of 
the c-Myc protein into cells to disrupt pathways 
stimulated by the normal, wild-type c-Myc. These 
experiments may reveal other protein factors that 
cooperate with c-Myc in controlling cell prolifer- 
ation and differentiation. We seek to understand 
how cells coordinate their functional maturation 
with a loss of ability to proliferate as they un- 
dergo the final stages of differentiation. 
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