FRAP DNA-dependent protein kinase mediates a late signal transduced from ultraviolet-induced DNA damage

Ultraviolet radiation induces signal transduction at both early (< 6 h) and late (> 6 h) times after exposure. The inflammatory and immunosuppressive cytokine tumor necrosis factor alpha is induced at late times, and is induc ed by ultraviolet-induced DNA damage, as defects in DNA repair increase, an d enhanced photoproduct repair reduces, tumor necrosis factor alpha express ion. Here we show that late tumor necrosis factor alpha gene expression is sensitive to rapamycin, implicating FKBP12-rapamycin-associated protein, a member of the DNA protein kinase family, as a signal transducer of ultravio let-induced DNA damage. FKBP12-rapamycin-associated protein was localized i n the nucleus of keratinocytes and its level was increased following ultrav iolet irradiation. Immuno- precipitated FKBP12-rapamycin-associated protein was stimulated by ultraviolet-irradiated DNA to phosphorylate p53 in vitro , and in vivo rapamycin reduced ultraviolet induction of p53 by 20%. Rapamy cin further inhibited the ultraviolet-induced phosphorylation of the FKBP12 -rapamycin-associated protein downstream target kinase p70(S6K.) In mice, t opical application of rapamycin before ultraviolet exposure protected again st suppression of the contact hypersensitivity that is a hallmark of ultrav iolet-induced cytokine gene expression. These results demonstrate that the FKBP12-rapamycin-associated DNA protein kinase transduces the signal of ult raviolet-induced DNA damage into production of immunosuppressive cytokines at late times after ultraviolet irradiation.