Induced telomerase activity in primary aortic endothelial cells by low-LET c-radiation is mediated through NF-kB activation

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 c-radiation can induce telomerase enzyme activity in primary aortic endothelial cells, and that an upstream regulator, nuclear factor kappa B (NF-kB), 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-kB becomes functionally activated upon radiation exposure and mediates the upregulation of telomerase activity by binding to the kB-binding region in the promoter region of the TERT gene. More significantly, elimination of the NF-kB recognition site on the telomerase promoter or inhibition of NF-kB by ectopically expressing the inhibitor protein IkBa mutant (IkBa) compromises radiationinduced telomerase promoter activation. Consistent with the notion that NF-kB mediates c-ray-induced telomerase responses, TRAP assay revealed that ectopically expressed IkBa also attenuated telomerase enzyme activity. These findings indicate that NF-kB activation following ionizing radiation exposure may elicit a survival advantage by upregulating and maintaining telomerase activity. Received 1 July 2007 Revised 28 November 2007 Accepted 10 December 2007 DOI: 10.1259/bjr/57867919 ’ 2008 The British Institute of