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First published online June 9, 2008
British Journal of Radiology (2008) 81, 711-720
© 2008 British Institute of Radiology
doi: 10.1259/bjr/57867919
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British Journal of Radiology 81 (2008),711-720 ©2008 The British Institute of Radiology

Full paper

Induced telomerase activity in primary aortic endothelial cells by low-LET {gamma}-radiation is mediated through NF-{kappa}B activation

M NATARAJAN 1,2 S MOHAN 3 R KONOPINSKI 1 R A OTTO 2 and T S HERMAN 4

Departments of 1 Radiation Oncology, 2 Otolaryngology Head and Neck Surgery, and 3 Pathology, The University of Texas Health Science Center, San Antonio, TX 78229 and 4 Radiation Oncology, The University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA

Correspondence: Mohan Natarajan, Associate Professor, Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. E-mail: Natarajan{at}uthscsa.edu

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-kcyB recognition site on the telomerase promoter or inhibition of NF-kcyB by ectopically expressing the inhibitor protein I{kappa}B{alpha} mutant (IkcyB{alpha}S32A/S36A)) 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.






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