Changes in environmental conditions such as the addition of growth fac
tors or irradiation of cells in culture first affect immediate respons
e genes. We have shown previously that short wavelength UV irradiation
(UVC) elicits massive activation of several growth factor receptor-de
pendent pathways. At the level of the immediate response gene c-fos, t
hese pathways activate the transcription factor complex serum response
factor (SRF)-p62(TCF) which mediates part of the UV-induced transcrip
tional response. These studies have, however, suggested that more that
one pathway is required for full UV responsiveness of c-fos. Using ap
propriate promoter mutations and dominant-negative cAMP response eleme
nt (CRE)-binding protein (CREB), we now find that UVC-induced transcri
ptional activation depends also on the CRE at position -60 of the c-fo
s promoter and on the functionality of a CREB. Upon UV irradiation, CR
EB and ATF-1 are phosphorylated at serines 133 and 63, respectively, p
receded by and dependent on activation of p38/RK/HOG-1 and of a p38/RK
/HOG-1-dependent p108 CREB kinase. Although p90(RSK1) and MAPKAP kinas
e 2 are also activated by UV, p90(RSK1) does not, at least not decisiv
ely, participate in this signalling pathway to CREB and ATF-1 as it is
not p38/RK/HOG-1 dependent, and CREB is a poor substrate for MAPKAP k
inase 2 in vitro. On the basis of resistance to the growth factor rece
ptor inhibitor suramin and of several types of cross-refractoriness ex
periments, the UVC-induced CREB/ATF-1 phosphorylation represents an as
yet unrecognized route of UVC-induced signal transduction, independen
t of suramin-inhibitable growth factor receptors and different from th
e Erk 1,2p62(TCF) pathway.