Journal
BRITISH JOURNAL OF RADIOLOGY
Volume 81, Issue 969, Pages 711-720Publisher
BRITISH INST RADIOLOGY
DOI: 10.1259/bjr/57867919
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Funding
- Office of Sciences (BER)
- US Department of Energy [DE-FG03-02ER63449]
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Our objective was to understand the mechanism through which cells that initially survive irradiation could acquire survival advantage. In this study, we show evidence that low-linear energy transfer gamma-radiation can induce telomerase enzyme activity in primary aortic endothelial cells, and that an upstream regulator, nuclear factor kappa B (NF-kappa B), controls this activation. Telomeric repeat amplification protocol (TRAP) assay showed that cells exposed to a dose of 2 Gy induce telomerase activity. Subsequent analysis revealed that radiation-induced telomeric activity is regulated at the transcriptional level by triggering activation of the promoter of the telomerase catalytic subunit, telomerase reverse transcriptase (TERT). A mechanistic study revealed that NF-kappa B becomes functionally activated upon radiation exposure and mediates the upregulation of telomerase activity by binding to the kappa B-binding region in the promoter region of the TERT gene. More significantly, elimination of the NF-kappa B recognition site on the telomerase promoter or inhibition of NF-kappa B by ectopically expressing the inhibitor protein I kappa B alpha mutant (I kappa B alpha(S32A/536A))) compromises radiation-induced telomerase promoter activation. Consistent with the notion that NF-kappa B mediates gamma-ray-induced telomerase responses, TRAP assay revealed that ectopically expressed I kappa B alpha(S32A/S36A)) also attenuated telomerase enzyme activity. These findings indicate that NF-kappa B activation following ionizing radiation exposure may elicit a survival advantage by upregulating and maintaining telomerase activity. (c) The British Institute of Radiology.
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