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 induced by ultraviolet-induced DNA damage, as defects in DNA repair increase, and enhanced photoproduct repair reduces, tumor necrosis factor alpha expression. 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 ultraviolet-induced DNA damage. FKBP12-rapamycin-associated protein was localized in the nucleus of keratinocytes and its level was increased following ultraviolet 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%. Rapamycin further inhibited the ultraviolet-induced phosphorylation of the FKBP12-rapamycin-associated protein downstream target kinase p70S6K. In mice, topical application of rapamycin before ultraviolet exposure protected against suppression of the contact hypersensitivity that is a hallmark of ultraviolet-induced cytokine gene expression. These results demonstrate that the FKBP12-rapamycin-associated DNA protein kinase transduces the signal of ultraviolet-induced DNA damage into production of immunosuppressive cytokines at late times after ultraviolet irradiation.
Yarosh
D B
DB
Applied Genetics Inc., Dermatics, Freeport, New York, New York, USA.
Cruz
P D
PD
Dougherty
I
I
Bizios
N
N
Kibitel
J
J
Goodtzova
K
K
Both
D
D
Goldfarb
S
S
Green
B
B
Brown
D
D
D004247:DNA / Q000528:radiation effects*; D004249:DNA Damage; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D003877:Dermatitis, Contact / Q000517:prevention & control; D005455:Fluorescent Antibody Technique; D006801:Humans; D020104:Immunophilins / Q000502:physiology*; D009687:Nuclear Proteins; D010766:Phosphorylation; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D022021:Tacrolimus Binding Proteins; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D014466:Ultraviolet Rays / Q000009:adverse effects*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D004247:DNA; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins; D020123:Sirolimus