Ionizing radiation induces expression and binding activity of the nuclear factor kappa B.

Abstract

Recent studies have demonstrated that treatment of mammalian cells with ionizing radiation is associated with activation of gene expression. Although the signal transduction pathways stimulated by ionizing radiation remain unclear, our previous findings indicate that radiation induces specific genes at the transcriptional level. The present work has examined the effects of ionizing radiation on the transcription factor NF-KB. The results demonstrate that ionizing radiation activates DNA binding of nuclear factor (NF),B. This effect was detectable at 2 grays (Gy) and reached a maximum at 5-20 Gy. At a dose of 20 Gy, the increase in NF-KB binding activity was maximal at 24 h and then declined to pretreatment levels. The results also demonstrate that ionizing radiation transiently increases NFxB mRNA levels. However, the finding that induction of NF-KB binding to DNA occurs in the presence of cycloheximide indicates that ionizing radiation activates preexisting NF-KB protein. NF-KB exists as a cytoplasmic protein before activation. Thus, our results suggest that ionizing radiation induces transduction pathways which include cytoplasmic sigaling events. (J. Clin. Invest. 1991. 88:691-695.)

Upregulation of cyclooxygenase-2 is accompanied by increased expression of nuclear factor-κB and IκB kinase-α in human colorectal cancer epithelial cells

“…(3) More recently, NF-kB constitutive activity, as observed in Hodgkin's lymphoma cells, has been associated with a mutation in the gene encoding the IkB-inhibitor (Krappmann et al, 1999), which can lead to impaired control of NF-kB activity and hence to enhanced nuclear activity (Bours et al, 2000). The NF-kB transcription factor is activated in response to a broad range of preapoptotic stimuli (Osborn et al, 1989;Brach et al, 1991;Schreck et al, 1991), dissociates from its attached inhibitory protein IkB and translocates to the nucleus to induce the expression of target genes, including several well-known antiapoptotic genes such as TNF-receptor-associated factor 1 (TRAF1), and TRAF2, cIAPs, manganese superoxide dismutase, A20 and IEX-IL (Wang et al, 1998;Wu et al, 1998). Although NF-kB has been previously shown to be expressed at high levels in human colonic adenomatous polyps, our investigations have demonstrated for the first time (to the best of our knowledge) that IKKa, cytoplasmic inactive NF-kB-p65 protein and putative active endonuclear NF-kB-p65 protein are significantly increased in malignant colorectal epithelial cells.…”

The ATM protein is required for sustained activation of NF-κB following DNA damage

“…NF-kB activation by oxidative stress has been widely documented (Sen and Packer, 1996;Flohe et al, 1997;Piette et al, 1997), and there is overwhelming evidence that oxidative stress causes DNA damage (Friedberg et al, 1995), mainly under the form of oxidized nucleic bases (like oxidation of guanine to 8-oxo-guanine), and strand breaks (leaving for instance a 3-phosphoglycolate terminus (Bertoncini and Meneghini, 1995)). We and others have shown previously that DNA-targeted lesions, probably strand breaks, activate NF-kB in leukaemic cells (Piret and Piette, 1996;Legrand-Poels et al, 1995;Brach et al, 1991;Kasibhatla et al, 1998). Other types of DNA-damaging agents can also activate NF-kB in some cell types (Quinto et al, 1993;Stein et al, 1989).…”

Function for p300 and not CBP in the apoptotic response to DNA damage

“…Whereas DNA-PK in turn phosphorylates and activates the pro-apoptotic c-Abl tyrosine kinase (Kharbanda et al, 1995Yuan et al, 1997), cAbl contributes to the transactivation function of the p53 tumor suppressor in the IR response (Sionov et al, 1999;Yuan et al, 1996). The nuclear factor kB is also activated by IR exposure (Brach et al, 1991;Mohan and Meltz, 1994;Wang et al, 1996). Other ®ndings that IR activates transcription of the c-jun and Egr-1 early response genes have supported the involvement of nuclear signals (Datta et al, 1992;Sherman et al, 1990).…”