PARENT SESSION
9:00 AM to 11:00 AM
Sunday, April 21, 2002
Symposium 5
Biologic Responses to Low Doses of Low LET Ionizing Radiation
Room: Nevada 6-7
Chair: Redpath, Les²²Department of Radiation Oncology, Irvine, CA, Co-Chair: Amundson, Sally³³National Institutes of Health, Bethesda, MD
Speakers: Amundson, Sally⁴; Boothman, David⁵; Joiner, Michael⁶; Redpath, Les⁷; Mitchel, Ronald⁸⁴National Institutes of Health, Bethesda, MD⁵Departments of Radiation Oncology and Pharmacology, Cleveland, OH⁶Dept of Radiation Biology, Detroit, MI⁷Department of Radiation Oncology, Irvine, CA⁸Department of Radiation Biology and Health Physics, Chalk River, ON

(S05-1) Gene expression in response to low dose ionizing radiation: A functional genomics approach.

Amundson, Sally^*,1, Koch-Paiz, Christine¹, Lee, R.¹, Fornace, Albert¹, ¹ National Cancer Institute, Bethesda, MD

ABSTRACT-
Changes in gene expression occur in both human and murine cells in response to doses of radiation of 10 cGy and less. Using a quantitative single-probe hybridization method to accurately measure increases in mRNA levels relative to untreated cells, we have demonstrated a linear non-threshold response for multiple stress genes in the human p53-wt myeloid ML-1 line, and in human peripheral blood lymphocytes (PBL) irradiated ex vivo. Similar responses are also emerging in mice irradiated in vivo. We have also used cDNA microarray hybridization analysis to identify radiation-regulated genes that could potentially serve as informative biomarkers of radiation exposure. Initial studies have identified several genes significantly up-regulated in human PBL between 24 and 72 hours after ex vivo irradiation. Three of these genes, DDB2, CDKN1A (CIP1/WAF1) and XPC, were induced in a linear fashion between 0.2 and 2 Gy at 24 and 48 hours after treatment, with less linearity at earlier or later times. Interestingly, these and other strongly radiation responsive genes are p53-regulated, indicating a major role for p53 in mediating radiation gene responses in PBL (and probably other primary cells). These results support the use of peripheral blood cells as an accessible and sensitive indicator of radiation exposure, and begin laying the foundation for expression profiles that may someday provide signatures for past radiation exposure. Reducing the dose-rate of exposure of ML-1 cells across 3 orders of magnitude shows a trend toward protection from apoptosis, and attenuated induction of GADD45A and CDKN1A. In contrast, there was no change in induction of MDM2. Clustering of cDNA microarray analysis results obtained from irradiations carried out at different dose-rates indicates two distinct groups of responding genes: a group of genes with attenuated induction at low dose-rates, and a group of genes with similar or possibly enhanced induction by low dose-rate exposure. Further analysis of these two classes of responding genes may provide key insights into the molecular mechanisms of radiation response and tolerance.

KEYWORDS: gene expression, microarray, dose-rate