CREB IS ACTIVATED BY UVC THROUGH A P38 HOG-1-DEPENDENT PROTEIN-KINASE/

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.