title: Global gene expression responses to low- or high-dose radiation in a human three-dimensional tissue model.
abstract: Accumulating data suggest that the biological responses to high and low doses of radiation are qualitatively different, necessitating the direct study of low-dose responses to better understand potential risks. Most such studies have used two-dimensional culture systems, which may not fully represent responses in three-dimensional tissues. To gain insight into low-dose responses in tissue, we have profiled global gene expression in EPI-200, a three-dimensional tissue model that imitates the structure and function of human epidermis, at 4, 16 and 24 h after exposure to high (2.5 Gy) and low (0.1 Gy) doses of low-LET protons. The most significant gene ontology groups among genes altered in expression were consistent with effects observed at the tissue level, where the low dose was associated with recovery and tissue repair, while the high dose resulted in loss of structural integrity and terminal differentiation. Network analysis of the significantly responding genes suggested that TP53 dominated the response to 2.5 Gy, while HNF4A, a novel transcription factor not previously associated with radiation response, was most prominent in the low-dose response. HNF4A protein levels and phosphorylation were found to increase in tissues and cells after low- but not high-dose irradiation.
authors.affiliation: Center for Radiological Research, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mezentsev
authors.forename: Sally A
authors.initials: SA
authors.lastname: Amundson
mesh_terms: D015153:Blotting, Western; D002454:Cell Differentiation / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism / Q000528:radiation effects*; D015870:Gene Expression / Q000528:radiation effects*; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000528:radiation effects; D045325:HCT116 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics; D006801:Humans; D016133:Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D016159:Tumor Suppressor Protein p53