TY - JOUR
T1 - Induced telomerase activity in primary aortic endothelial cells by low-LET γ-radiation is mediated through NF-κB activation
AU - Natarajan, Mohan
AU - Mohan, S.
AU - Konopinski, R.
AU - Otto, R. A.
AU - Herman, T. S.
PY - 2008/9
Y1 - 2008/9
N2 - 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-κB), 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-κB becomes functionally activated upon radiation exposure and mediates the upregulation of telomerase activity by binding to the κB-binding region in the promoter region of the TERT gene. More significantly, elimination of the NF-κB recognition site on the telomerase promoter or inhibition of NF-κB by ectopically expressing the inhibitor protein IκBα mutant (IκBαS32A/S36A)) compromises radiation-induced telomerase promoter activation. Consistent with the notion that NF-κB mediates γ-ray-induced telomerase responses, TRAP assay revealed that ectopically expressed IκBα S32A/S36A) also attenuated telomerase enzyme activity. These findings indicate that NF-κB activation following ionizing radiation exposure may elicit a survival advantage by upregulating and maintaining telomerase activity.
AB - 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-κB), 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-κB becomes functionally activated upon radiation exposure and mediates the upregulation of telomerase activity by binding to the κB-binding region in the promoter region of the TERT gene. More significantly, elimination of the NF-κB recognition site on the telomerase promoter or inhibition of NF-κB by ectopically expressing the inhibitor protein IκBα mutant (IκBαS32A/S36A)) compromises radiation-induced telomerase promoter activation. Consistent with the notion that NF-κB mediates γ-ray-induced telomerase responses, TRAP assay revealed that ectopically expressed IκBα S32A/S36A) also attenuated telomerase enzyme activity. These findings indicate that NF-κB activation following ionizing radiation exposure may elicit a survival advantage by upregulating and maintaining telomerase activity.
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U2 - 10.1259/bjr/57867919
DO - 10.1259/bjr/57867919
M3 - Article
C2 - 18541630
AN - SCOPUS:51349098241
SN - 0007-1285
VL - 81
SP - 711
EP - 720
JO - British Journal of Radiology
JF - British Journal of Radiology
IS - 969
ER -