UVB-induced activation of NF-kappaB is regulated by the IGF-1R and dependent on p38 MAPK.
To manage the frequent exposure to carcinogenic UVB wavelengths found in sunlight, keratinocytes have extensive protective measures to handle UVB-induced DNA damage. Recent in vitro evidence and epidemiological data suggest that one possible protective mechanism is dependent on the functional status of the IGF-1R signaling network. A second important signaling pathway regulating the response of keratinocytes to UVB involves the activation of the NF-kappaB transcription factor. Although it is clear that proper functioning of both the IGF-1R and NF-kappaB signaling networks are critical for the appropriate response of keratinocytes to UVB irradiation, it is currently uncertain if these two pathways interact. We now demonstrate that the activation of the NF-kappaB transcription factor by UVB is altered by the functional status of the IGF-1R. In the absence of ligand-activated IGF-1R, UVB-induced NF-kappaB consisted primarily of p50:p50 homodimers. Furthermore, the p38 kinase MAPK directs the subunit composition of NF-kappaB following UVB irradiation, most likely in an IGF-1R-dependent manner. We hypothesize that UVB irradiation leads to an activated p38 MAPK that is regulated in an IGF-1R-dependent manner, leading to NF-kappaB p50:RelA/p65 activation and a survival phenotype. In the absence of ligand-activated IGF-1R, UVB irradiation leads to the induction of NF-kappaB p50:p50 homodimers and a p38-dependent increased susceptibility to apoptosis.
Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Davina A
DA
Lewis
Dan F
DF
Spandau
D017209:Apoptosis; D002478:Cells, Cultured; D019281:Dimerization; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000528:radiation effects*; D016328:NF-kappa B / Q000378:metabolism / Q000528:radiation effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D017526:Receptor, IGF Type 1; D048051:p38 Mitogen-Activated Protein Kinases