Linked Life Data

12692264

Source:http://linkedlifedata.com/resource/pubmed/id/12692264

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2003-4-14
pubmed:abstractText
In the past, most mechanistic studies of ionizing radiation response have employed very large doses, then extrapolated the results down to doses relevant to human exposure. It is becoming increasingly apparent, however, that this does not give an accurate or complete picture of the effects of most environmental exposures, which tend to be of low dose and protracted over time. We have initiated direct studies of low dose exposures, and using the relatively responsive ML-1 cell line, have shown that changes in gene expression can be triggered by doses of gamma-rays of 10 cGy and less in human cells. We have now extended these studies to investigate the effects on gene induction of reducing the rate of irradiation. In the ML-1 human myeloid leukemia cell line, we have found that reducing the dose rate over three orders of magnitude results in some protection against the induction of apoptosis, but still causes linear induction of the p53-regulated genes CDKN1A, GADD45A, and MDM2 between 2 and 50 cGy. Reducing the rate of exposure reduces the magnitude of induction of CDKN1A and GADD45A, but not the magnitude or duration of cell cycle delay. In contrast, MDM2 is induced to the same extent regardless of the rate of dose delivery. Microarray analysis has identified additional low dose-rate-inducible genes, and indicates the existence of two general classes of low dose-rate responders in ML-1. One group of genes is induced in a dose rate-dependent fashion, similar to GADD45A and CDKN1A. Functional annotation of this gene cluster indicates a preponderance of genes with known roles in apoptosis regulation. Similarly, a group of genes with dose rate-independent induction, such as seen for MDM2, was also identified. The majority of genes in this group are involved in cell cycle regulation. This apparent differential regulation of stress signaling pathways and outcomes in response to protracted radiation exposure has implications for carcinogenesis and risk assessment, and could not have been predicted from classical high dose studies.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
1541-7786
pubmed:author
pubmed:issnType
Print
pubmed:volume
1
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
445-52
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:12692264-Apoptosis, pubmed-meshheading:12692264-Cell Cycle, pubmed-meshheading:12692264-Cell Cycle Proteins, pubmed-meshheading:12692264-Cell Line, Tumor, pubmed-meshheading:12692264-Cyclin-Dependent Kinase Inhibitor p21, pubmed-meshheading:12692264-Cyclins, pubmed-meshheading:12692264-Dose-Response Relationship, Radiation, pubmed-meshheading:12692264-Gamma Rays, pubmed-meshheading:12692264-Gene Expression Profiling, pubmed-meshheading:12692264-Gene Expression Regulation, Neoplastic, pubmed-meshheading:12692264-Humans, pubmed-meshheading:12692264-Nuclear Proteins, pubmed-meshheading:12692264-Oligonucleotide Array Sequence Analysis, pubmed-meshheading:12692264-Proto-Oncogene Proteins, pubmed-meshheading:12692264-Proto-Oncogene Proteins c-mdm2, pubmed-meshheading:12692264-Time Factors, pubmed-meshheading:12692264-Transcriptional Activation
pubmed:year
2003
pubmed:articleTitle
Differential responses of stress genes to low dose-rate gamma irradiation.
pubmed:affiliation
Division of Basic Science, National Cancer Institute and National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. amundson@box-a.nih.gov
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S.