Office of Biological and Environmental Research

DOE Low Dose Radiation Program Workshop IV

Abstract

Title: Gene Expression Profiles of Human Skin Keratinocytes Exposed to Acute and Chronic Ionizing Radiation

Authors: Jian Jian Li,¹ Munetaka Ozeki,¹ Tieli Wang,¹ Daniel Tamae,¹ Dave Nelson,² Andrew Wyrobek,² and Matthew A. Coleman²

Institutions: ¹Radiation Biology Section, Division of Radiation Oncology Beckman Research Institute, City of Hope National Medical Center, Duarte, California; and 2BBRP, Lawrence Livermore National Laboratory, Livermore, California

Running Title: Radiation Induced Gene Expression Pattern in Human Skin Cells

Molecular mechanisms underlying radiation responses and the signaling network causing cell adaptive radioprotection remain to be elucidated. We have shown that transcription factor NF-_KB is a sensor gene regulator to ionizing radiation (IR) and that a group of pro-survival genes regulated by NF-_KB is activated with an enhanced survival of human keratinocytes following chronic exposure of IR (HK18+FIR). Since the parental human keratinocyte line (HK18) was infected with HPV18 genome causing inactive TP53, the HK18+FIR cell model provides a unique approach to investigating the IReffector genes responsive to NF-_KB-mediated adaptive responses. To further describe NF- KB-regulated gene expression, profiles in human skin cells exposed to one vs. multiple IR doses are compared. The current project carried out by a combined research group with expertise in signal transduction and DNA microarrays, is to investigate the following data of gene expression patterns in parental HK18 and chronic IR-adapted HK18+FIR cell lines: a) HK18 vs. HK18+2Gy; b) HK18 vs. HK18+FIR; c) HK18+FIR vs. HK18+FIR+2Gy; and d) HK18+FIR+mIKB vs. HK18+FIR+mIKB+2Gy. Using cluster analysis tools each paired profiles obtained from 22,284-globe gene microarray, we are focusing on obtaining an in vitro NF-_KB gene response pattern in human skin epithelial cells following low (1-10 cGy) or high (200 -1000 cGy) of single and/or multiple doses of IR. With statistical Qc and F-test analysis (p < 0.05), we are testing if a group of IR-responsive genes are mediated by activation of NF-_KB. These results should provide a basis for further analysis of IR-adaptive protection signaling profiles and may promise the generation of specific gene targets useful for enhancing skin IR tolerance.

This work was performed under the auspices of the U.S. Department of Energy by the University of California, Lawrence Livermore National Laboratory under Contract No. W-7405-Eng-48 with funding from the DOE Low Dose Radiation Research Program.

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