Inhibition of Rel/Nuclear Factor-kappaB signaling in skin results in defective DNA damage-induced cell cycle arrest and Ha-ras- and p53-independent tumor development.
In recent years a growth inhibitory role in skin for the Rel/NF-kappaB transcription factors has been established, and the block of Rel/NF-kappaB signaling results in rapid development of spontaneous skin cancer. The molecular mechanism underlying tumor development is however unknown. In the present study, we show that inhibition of NF-kappaB signaling in mouse skin by targeted expression of degradation resistant IkappaB-alpha generates transgenic keratinocytes unable to arrest the cell cycle in response to DNA damage induced by gamma-radiation. The results indicate that transgenic keratinocytes have a defect at the G1-S checkpoint whereas the G2-M checkpoint response was found to be intact. However, transgenic keratinocytes still respond by induction of the cyclin dependent kinase inhibitor p21(Cip1/Waf) after exposure to gamma-radiation. In the spontaneous skin tumors that develop in transgenic mice no mutations were found in the Ha-ras or p53 gene, suggesting that inhibition of NF-kappaB signaling in skin can induce cancer development independently of initiating mutations in the Ha-ras gene or additional mutations in the p53 gene. These findings demonstrate an involvement of NF-kappaB signaling in the DNA damage response and cell cycle checkpoint control in the skin.
Department of Bioscience at Novum, Karolinska Institutet, NOVUM, SE-141 57 Huddinge, Sweden.
Max
M
van Hogerlinden
Gert
G
Auer
Rune
R
Toftgård
D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D004249:DNA Damage; D011905:Genes, ras / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020572:Oncogene Proteins v-rel / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D016328:NF-kappa B; D020572:Oncogene Proteins v-rel; D016159:Tumor Suppressor Protein p53