Inhibition of Rel/Nuclear Factor-κB signaling in skin results in defective DNA damage-induced cell cycle arrest and Ha-ras- and p53-independent tumor development

Abstract

In recent years a growth inhibitory role in skin for the Rel/NF-kB transcription factors has been established, and the block of Rel/NF-kB 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-kB signaling in mouse skin by targeted expression of degradation resistant IkB-a generates transgenic keratinocytes unable to arrest the cell cycle in response to DNA damage induced by g-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 g-radiation. In the spontaneous skin tumors that develop in transgenic mice no mutations were found in the Haras or p53 gene, suggesting that inhibition of NF-kB 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-kB signaling in the DNA damage response and cell cycle checkpoint control in the skin.

Tumor necrosis factor receptor 1-mediated signaling is required for skin cancer development induced by NF-κB inhibition

“…In this setting, expression of I B␣ was shown to cause an up-regulation of cyclin-dependent kinase 4 (Cdk4). We have previously shown that the tumors in the K5-I B␣ mice do not display mutations in Ha-Ras (16). Nor could we detect any increase in active MAPK in skin or in tumors from K5-I B␣ mice compared to wild-type skin (Fig.…”

“…We have previously reported that keratinocytes in K5-I B␣ mice show an abnormal cell cycle arrest in response to gamma irradiation (16). The effect is only seen in hyperplastic, inflamed skin whereas primary keratinocytes isolated from K5-I B␣ mice grown in vitro respond normally to ␥ irradiation (data not shown), suggesting that inflammation and͞or increased expression of cytokines contribute to the altered DNA-damage response in the K5-I B␣ mice.…”

The NF-κB-mediated control of the JNK cascade in the antagonism of programmed cell death in health and disease

“…3,12,16 For instance, despite its well-established role in oncogenesis and tumor progression in various tissues, NFkB promotes growth arrest, differentiation and tumor suppression in epidermal keratinocytes. 16,105,143,144 Indeed, a prolonged inhibition of NF-kB in these cells results in formation of squamous cell carcinoma and can act synergistically with oncogenic H-ras to induce malignant transformation. 16,105,143,144 NF-kB might exert a similar tumor-suppressor function also in the liver, because (while impeding tumor progression) conditional deletion of IKKb in hepatocytes appears to enhance tumor initiation in a model of chemical carcinogenesis.…”

Nuclear Factor-κB Enhances ErbB2-Induced Mammary Tumorigenesis and Neoangiogenesis in Vivo

“…Anti-inflammatory drugs that are known to inhibit IKK-dependent NF-B activity reduced the cumulative incidence of colitis-associated cancer in patients with ulcerative colitis, suggesting a role for NF-B in colonic tumor onset and/or progression. 4 In contrast, inhibition of NF-B in vivo promoted squamous cell tumors, [5][6][7] indicating the possibility of cell-type-specific roles for NF-B in tumorigenesis. Inactivation of I⌲K␤ in intestinal epithelial cells reduced colonic tumor formation in response to chemical procarcinogens, 8 implying that I⌲K␤ plays a key role in promoting enterocyte tumorigenesis.…”