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DOE Low Dose Radiation Program WorKshop IV

Abstract

Title: Radiation-Induced Nuclear Factor kB mediates survival advantage by Telomerase Activation.

Authors: Natarajan M.,¹ Mohan S.,² Pandeswara, S.L.,¹ and Herman T.S.¹

Institutions: Departments of ¹Radiation Oncology and ²Pathology, The University of Texas Health Science Center, San Antonio, Texas

Activation of NF-kB in response to low doses of ionizing radiation was first shown in our laboratory. Although studies have shown that NF-kB plays an important role in anti-apoptotic function, little has been done to understand the molecular link between the activation of NF-kB and cellular outcome such as enhanced cell survival after low dose low-linear transfer (LET) radiation. Because upregulation of telomerase activity is associated with longevity and allows cells to escape from senescence, we hypothesize that low dose radiation-induced NF-kB signaling could mediate telomerase activation and thus confer enhanced cell survival of normal aortic endothelial cells. Telomeric Repeat Amplification Protocol (TRAP) assay following exposure to 10 cGy showed an increase in telomerase enzyme activity as early as 8 hours post irradiation and reaches its maximum at 24 hours. Subsequent analysis revealed that the increased telomerase enzyme activity is due to increased synthesis resulting from an increased transcription. Examination of transcriptional activation of telomerase reverse transcriptase (TERT) promoter regulation showed an enhanced transcription of the telomerase gene following irradiation. Next, to determine whether the 10 cGy-induced activation of NF-kB-signaling is responsible for induced TERT promoter activation, cells transiently transfected with minimal promoter region of TERT containing wild-type or mutant NF-kB binding sites were examined following exposure to 10 cGy. The TERT promoter activation was induced in wild-type transfected cells, whereas in mutant kB binding site, the activation remained at the basal level, similar to that of mock-irradiated cells. More significantly, the radiation-mediated promoter activation of telomerase gene as well as induced telomerase enzyme activity were abrogated by ectopically expressing the IkB-a mutant (IkB-a (S32A/S36A), which blocks NF-kB activation. These results thus suggest that exposure to low-LET radiation could induce telomerase activity and the activation is at least, in part, mediated by the transcription factor NF-kB. Sustained activation of telomerase in these cells after low-LET radiation may impart extended life span.

This Research was supported by the Office of science (BER), U.S Department of Energy Grant No. DEFG03- 02ER63449-02ER63449.

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