title: ATM-dependent and -independent gene expression changes in response to oxidative stress, gamma irradiation, and UV irradiation.
abstract: Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by progressive cerebellar degeneration, immunodeficiencies, telangiectasias, sensitivity to ionizing radiation, and high predisposition for malignancies. The ataxia telangiectasia mutated (ATM) gene encodes a protein (ATM) with serine/threonine kinase activity. DNA-double strand breaks are known to increase its kinase activity. While cells from individuals with AT are attenuated in their G(1)-, S- and G(2)-phase cell cycle checkpoint functions in response to gamma irradiation and oxidative stress, their response to UV irradiation appears to be equivalent to that of wild-type cells. In this study, we investigated changes in gene expression in response to gamma irradiation, oxidative stress, and UV irradiation, focusing on the dependence on ATM. Doses for all three treatments were selected that resulted in roughly an equivalent induction of a G(1) checkpoint response and inhibition of progression through S phase. To investigate gene expression changes, logarithmically growing wild-type and AT dermal diploid fibroblasts were exposed to either gamma radiation (5 Gy), oxidative stress (75 micro M t-butyl-hydroperoxide), or UV radiation (7.5 J/m(2)), and RNA was harvested 6 h after treatment. Gene expression analysis was performed using the NIEHS Human ToxChip 2.0 with approximately 1900 cDNA clones representing known genes and ESTs. All three treatments resulted in distinct patterns of gene expression changes, as shown previously. ATM-dependent and ATM-independent components were detected within these patterns, as were novel indications of involvement of ATM in regulation of transcription factors such as SP1, AP1 and MTF1.
authors.affiliation: Growth Control and Cancer Group, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Alexandra N
authors.initials: AN
authors.lastname: Heinloth
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Shackelford
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Innes
authors.forename: Lee
authors.initials: L
authors.lastname: Bennett
authors.forename: Leping
authors.initials: L
authors.lastname: Li
authors.forename: Rupesh P
authors.initials: RP
authors.lastname: Amin
authors.forename: Stella O
authors.initials: SO
authors.lastname: Sieber
authors.forename: Kristina G
authors.initials: KG
authors.lastname: Flores
authors.forename: Pierre R
authors.initials: PR
authors.lastname: Bushel
authors.forename: Richard S
authors.initials: RS
authors.lastname: Paules
mesh_terms: D000465:Algorithms; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002460:Cell Line; D002478:Cells, Cultured; D019927:Cyclin E / Q000378:metabolism; D004249:DNA Damage; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D020224:Expressed Sequence Tags; D005347:Fibroblasts / Q000378:metabolism; D016193:G1 Phase; D016195:G2 Phase; D005720:Gamma Rays; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics*; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D014466:Ultraviolet Rays; D015854:Up-Regulation
chemical_list: D018797:Cell Cycle Proteins; D019927:Cyclin E; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D006657:Histones; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D012313:RNA; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases