REGULATION OF EARLY-RESPONSE GENES 
Although the typical early-response gene is induced rapidly and transiently, 
the magnitude and the time course of induction can vary. For instance, c -fos 
transcription can be detected within 5 minutes of stimulation, but expression is 
typically shut off at the transcriptional level by 1 hour. The messenger RNA 
for c -fos is unstable, and the persistence of the message is less than 2 hours 
(Greenberg and Ziff 1984; Muller et al. 1984). This could be compared with the 
JE gene in fibroblast, which is transcriptionally induced rapidly by 30 minutes, 
but which is still being transcribed up to 6 hours postinduction (Cochran et 
al. 1988). Absolute levels of induction of these genes can vary greatly; for 
example, the c -myc gene is induced only to a level of 30 to 50 copies per cell, 
whereas the c -fos gene is present transiently at 20 times that level (Cochran 
et al. 1988; Kelly et al. 1983). For individuals of the same gene family such as 
the fos-related genes, the time courses can also vary. The time course of the 
fra genes appears to be slower and longer than those of fos\ this may have a 
physiological significance for the type of AP-1 complexes present in the cell at 
a given time, since it has been shown that the subunits of AP-1 complex can 
interchange rapidly in solution (Kovary and Bravo 1991 ; Ryseck and Bravo 
1991 ; Sonnenberg et al. 1989a). The mechanisms responsible for the transient 
expression of lEGs also may vary. One mechanism by which transient 
expression is maintained is autorepression of a promoter by its own gene 
product. For instance, c -fos and in some cases c-myc can autoregulate their 
own synthesis (Penn et al. 1990; Sassone-Corsi et al. 1988a). Another 
mechanism by which expression may be shut off may be simply the down- 
regulation of the second signal stimuli, either at the level of the receptor or at 
the level of second messenger. 
Most lEGs are capable of responding to a variety of extracellular stimuli. 
In fibroblasts these agents Include not only growth factors such as PDGF, 
fibroblast growth factor, and epidermal growth factor (EGF), but also agents 
such as phorbol esters and bombesin that can induce IEG expression 
through non-tyrosine-kinase-type receptors (Lim et al. 1987; Rabin et al. 
1986). Calcium ionophores and agents that affect cyclic AMP (cAMP) levels 
within the cell can induce expression of some lEGs (Almendral et al. 1988; 
Morgan and Curran 1986; Ran et al. 1986; Sheng et al. 1988). In PCI 2 cells, it 
has been shown that lEGs can be induced by neurotransmitters, by membrane 
depolarization, and by various manipulations of extracellular ions and ion 
channels (Curran and Morgan 1985; Greenberg et al. 1985; Kruijer et al. 1985; 
Morgan and Curran 1986). Moreover, a variety of recent studies have shown 
that activated oncogenes such as ras and src can induce many of these same 
early-response genes (Jahner and Hunter 1991b; Stacey et al. 1987). This 
observation is not surprising considering that many of the activated oncogenes 
are components of signal transduction pathways. 
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