The role of PI 3-kinase in the UVB-induced expression of c-fos.

The role of the PI 3-kinase signaling pathway in UVB-induced c-fos gene expression was investigated in a human keratinocyte cell line, HaCaT. The enzymatic activity of PI 3-kinase was increased threefold by 250 J/m(2) UVB. Inhibition of PI 3-kinase activity, via expression of a mutant p85 subunit or treatment with wortmannin, resulted in decreased levels of c-fos promoter activity and c-fos protein. Two members of the PI 3-kinase signaling pathway, Akt and GSK-3beta, were also found to affect c-fos transactivation. Expression of dominant negative Akt or wild-type GSK-3beta significantly inhibited UVB-induced c-fos promoter activity. In addition, when GSK-3beta activity was inhibited by lithium chloride, both c-fos promoter activity and protein levels increased. These results demonstrate that both Akt activation and GSK-3beta inactivation are required in the UVB-induction of c-fos. Our results demonstrate for the first time that UVB induction of c-fos is in part mediated by the PI 3-kinase signaling pathway in the HaCaT cell line. By identifying the multiple signaling pathways that are induced by UVB and contribute to the induction of c-fos expression, more drug targets may be identified to aid attempts to prevent and treat skin cancer.