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. 1999 Dec 8;82(1):28–33. doi: 10.1054/bjoc.1999.0872

Inhibition of I κ B-α phosphorylation at serine and tyrosine acts independently on sensitization to DNA damaging agents in human glioma cells

J Miyakoshi 1, K Yagi 2
PMCID: PMC2363178  PMID: 10638962

Abstract

Molecular mechanisms and/or intrinsic factors controlling cellular radiosensitivity are not fully understood in mammalian cells. The recent studies have suggested that nuclear factor κB (NF-κB) is one of such factors. The activation and regulation of NF-κB are tightly controlled by IκB-α, a cellular inhibitory protein of NF-κB. Most importantly, phosphorylation regulates activity of the inhibitor IκB-α, which sequesters NF-κB in the cytosol. Two different pathways for the phosphorylation of IκB-α are demonstrated, such as serine (at residues 32 and 36) and tyrosine (at residue 42) phosphorylations. To assess a role of the transcription factor, NF-κB, on cellular sensitivity to DNA damaging agents, we constructed three different types of expression plasmids, i.e. S-IκB (mutations at residues 32 and 36), Y-IκB (mutation at residue 42) and SY-IκB (mutations at residues 32, 36 and 42). The cell clones expressing S-IκB and Y-IκB proteins became sensitive to X-rays as compared with the parental and vector-transfected cells. The cell clones expressing SY-IκB were further radiosensitive. By the treatment with herbimycin A, an inhibitor of phosphorylation, the X-ray sensitivity of cells expressing SY-IκB did not change, while that of the cells expressing S-IκB and Y-IκB and the parental cells was enhanced. Change in the sensitivity to adriamycin and UV in those clones was very similar to that in the X-ray sensitivity. The inhibition of IκB-α phosphorylation at serine and tyrosine acts independently on the sensitization to X-rays, adriamycin and UV. These findings suggest that the transcriptional activation induced by NF-κB may play a role in the DNA damage repair. The present study proposes a possibility that the inactivation of NF-κB by inhibition of both serine and tyrosine phosphorylations may be useful for the treatment of cancer in radio- and chemotherapies. © 2000 Cancer Research Campaign

Keywords: IκB-α, NF-κB, phosphorylation, DNA damaging agents, human glioma cells

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Selected References

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