Not all lEGs are coordinately regulated. Different stimuli can elicit different 
patterns of expression of the lEGs in the same cell type. C-/bs is induced 
readily by phorbol esters in fibroblasts, but the JE and KC genes are not (Hall 
and Stiles 1987). Conversely, in 3T3 fibroblasts, interleukin-1 can induce JE 
and KC but have little effect on c-/bs (Hall et al. 1989). Moreover, a given 
stimulus can have dramatically different effects on different cell types. In PCI 2 
cells, c -fos is induced by calcium ionophores as well as by EGF (Greenberg et 
al. 1985; Kruijer et al. 1985). However, in Balb/c-3T3 cells, calcium Ionophores 
and EGF are very weak inducers of fos (Hall and Stiles 1987). In addition, it is 
clear that different stimuli can induce a similar set of genes in a given cell and 
yet have different effects. This can be dramatically visualized in studies of 
PCI 2 cells, for which EGF is a mitogen and NGF can induce differentiation. 
Both of these factors can induce c -fos and c-myc in these cells, but only NGF 
produces neurite outgrowth (Greenberg et al. 1985). The difference between 
these responses must result from differing second signals generated by these 
two factors, even though some of the second signals are likely to overlap. 
Differences in signals could include the activation of different kinases and 
phosphorylation of different substrates as well as activation of genes uniquely 
by one factor or the other. To understand the complex regulation of lEGs, it will 
be necessary to understand both the second signals generated by any given 
stimulus and the regulatory elements that control the expression of each of 
these genes. 
Second messenger systems to which early-response genes can respond are 
numerous and varied. The fact that phorbol esters such as phorbol myristoy 
acetate can induce c -fos and c-jun indicates that activation of protein kinase 
C is one of the pathways by which lEGs are induced (Lamph et al. 1988; Rabin 
et al. 1986). The observation that a calcium ionophore such as A23187 can 
induce c -fos in some cells indicates that calcium can be a second messenger 
for the induction of some early-response genes. In PCI 2 cells there is 
evidence to suggest that the opening of a voltage-gated calcium channel can 
induce c -fos (Morgan and Curran 1986). lEGs such as c-fos and jun - B can 
respond to agents such as forskolin and isobutyl methyl xanthine, which 
increase intracellular cAMP concentrations (Berkowitz et al. 1989; Fisch et al. 
1989a; Sassone-Corsi et al. 1988b). In addition, it is clear that second signal 
pathways activated by other kinases can induce early-response genes. This 
is indicated by the fact that cotransfection or microinjection of genes such as 
c-rafand activation of a temperature-sensitive c-srcgene can induce a broad 
spectrum of early-response genes (Jahner and Hunter 1991b; Jamal and Ziff 
1990; Kaibuchi et al. 1989). Moreover, activated ras, a G protein, can induce 
at least c -fos (Fukumoto et al. 1990; Gauthier et al. 1990; Stacey et al. 1987). 
Thus, the ras - activated signaling pathway appears to be another mechanism 
by which some early-response genes can be activated. 
8 
