Changes in environmental conditions such as the addition of growth factors or irradiation of cells in culture first affect immediate response genes. We have shown previously that short wavelength UV irradiation (UVC) elicits massive activation of several growth factor receptor‐dependent pathways. At the level of the immediate response gene c‐fos, these pathways activate the transcription factor complex serum response factor (SRF)–p62TCF which mediates part of the UV‐induced transcriptional response. These studies have, however, suggested that more that one pathway is required for full UV responsiveness of c‐fos. Using appropriate promoter mutations and dominant‐negative cAMP response element (CRE)‐binding protein (CREB), we now find that UVC‐induced transcriptional activation depends also on the CRE at position −60 of the c‐fos promoter and on the functionality of a CREB. Upon UV irradiation, CREB and ATF‐1 are phosphorylated at serines 133 and 63, respectively, preceded by and dependent on activation of p38/RK/HOG‐1 and of a p38/RK/HOG‐1‐dependent p108 CREB kinase. Although p90RSK1 and MAPKAP kinase 2 are also activated by UV, p90RSK1 does not, at least not decisively, 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 kinase 2 in vitro. On the basis of resistance to the growth factor receptor inhibitor suramin and of several types of cross‐refractoriness experiments, the UVC‐induced CREB/ATF‐1 phosphorylation represents an as yet unrecognized route of UVC‐induced signal transduction, independent of suramin‐inhibitable growth factor receptors and different from the Erk 1,2–p62TCF pathway.
IκBα is an inhibitor protein that prevents nuclear transport and activation of the transcription factor NF‐κB. In acute inflammation, NF‐κB is activated and increases the expression of several pro‐inflammatory cytokine and chemokine genes. Glucocorticoids counteract this process. It has been proposed that the glucocorticoid‐dependent inhibition of NF‐κB activity is mediated by increased synthesis of IκBα which should then sequester NF‐κB in an inactive cytoplasmic form. Here, we show by the use of a mutant glucocorticoid receptor and steroidal ligands that hormone‐induced IκBα synthesis and inhibition of NF‐κB activity are separable biochemical processes. A dimerization‐defective glucocorticoid receptor mutant that does not enhance the IκBα level is still able to repress NF‐κB activity. Conversely, glucocorticoid analogues competent in enhancing IκBα synthesis do not repress NF‐κB activity. These results demonstrate that increased synthesis of IκBα is neither required nor sufficient for the hormone‐mediated downmodulation of NF‐κB activity.
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