Differential inhibition of UVB-induced AP-1 and NF-kappaB transactivation by components of the jun bZIP domain.
Potential targets for chemoprevention of nonmelanoma skin cancer include UV-induced nuclear factor kappaB (NF-kappaB) and activator protein-1 (AP-1) activation in keratinocytes. Inhibition of both these ultraviolet light B (UVB)-induced transcription factors has been shown with the dominant-negative c-jun mutant, TAM67; however, its mechanism of action has not yet been determined. Here we demonstrated that transient transfection of a mouse keratinocyte cell line (308) with a dominant-negative phosphorylation mutant of c-Jun before exposure to 250 J/m(2) UVB inhibits transactivation mediated by both AP-1 and NF-kappaB transcription factors to levels below those of UVB exposed controls. Through the utilization of immunoprecipitation techniques, protein-protein interactions between NF-kappaB family members IkappaBalpha, IkappaBbeta, p50, and p65 (Rel-A) were identified with an Xpress tagged dominant-negative c-Jun (TAM67) protein. Expression of the leucine zipper domain of the TAM67 protein inhibited UVB-induced NF-kappaB transactivation but not AP-1 transactivation. Expression of the bZIP domain of the TAM67 protein was able to inhibit transactivation mediated by both transcription factors. These data demonstrate that TAM67 is able to inhibit two significant UVB-induced molecular targets AP-1 and NF-kappaB, and that the inhibition of these two transcription factor families is potentially due to protein-protein interactions between different regions of the dominant-negative c-Jun protein.
Cooper
Simon
S
Arizona Cancer Center, Tucson, Arizona 85724, USA.
Ranger-Moore
James
J
Bowden
Tim G
TG
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000502:physiology / Q000528:radiation effects; D016758:Genes, jun / Q000528:radiation effects*; D015603:Keratinocytes; D051379:Mice; D016328:NF-kappa B / Q000235:genetics* / Q000528:radiation effects; D009687:Nuclear Proteins / Q000528:radiation effects*; D010446:Peptide Fragments / Q000235:genetics / Q000528:radiation effects; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000528:radiation effects; D016601:RNA-Binding Proteins / Q000528:radiation effects*; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000528:radiation effects; D014157:Transcription Factors / Q000528:radiation effects*; D015533:Transcriptional Activation / Q000528:radiation effects*; D014466:Ultraviolet Rays
C105242:ALYREF protein, human; D016328:NF-kappa B; D009687:Nuclear Proteins; D010446:Peptide Fragments; D016755:Proto-Oncogene Proteins c-jun; D016601:RNA-Binding Proteins; C439528:TAM67 peptide; D018808:Transcription Factor AP-1; D014157:Transcription Factors