The long-term goal of this research program is to gain knowledge concerning the mechanisms involved in the response of mammalian cells to ionizing radiation, with particular reference to its carcinogenic and mutagenic effects. The approach is a multi-faceted one, and the endpoints under investigation include mutagenesis, malignant transformation, cell survival and the induction of chromosomal abnormalities. The program has the overall purpose of further defining the risks of low-level radiation exposure by gaining a better understanding of the cellular and molecular mechanisms for its effects. A particular focus is on the induction of genetic instability by radiation, and the role that homologous recombinational events may play in this process.
The Specific Aims are: 1) To identity oncogenes activated or expressed during the process of malignant transformation induced by radiation, by use of denaturing gradient gel electrophoresis blots and subtraction cloning by the representational differences analysis (RDA) technique; 2) To examine the role of genome-wide instability in malignant transformation, in particular to seek evidence for the involvement of homologous recombination in this process; genetic rearrangements will be examined in minisatellite loci as well as random DNA sequences. 3) To examine the recombinogenic potential of several classes of agents in an assay for measuring interallelic homologous recombination in human cells developed during the prior grant period, including the phorbol ester tumor promoter TPA and radiation; 4) To seek evidence for coincident or second site mutations in a group of random, non-selected microsatellite loci in cells selected for mutations at the tk locus; 5) To better characterize the delayed mutagenic effects of radiation by examining the molecular structure of late-arising mutations and identifying the gene(s) that may be induced or activated by radiation in mutator clones; 6) To examine further the mechanism for the effect of SV40 large T antigen on radiosensitivity, by use of a large panel of T-antigen mutants containing single-base point mutations in specific sequences of the various functional domain of the gene; and 7) To determine whether specific mRNAs are expressed in alpha irradiated cells by use of the differential display technique, in order to identity genes that may be turned on in response specifically to alpha radiation.
|Little, J B (2007) [Nontargeted effects of ionizing radiation: implications for low-dose exposures] Radiats Biol Radioecol 47:262-72|
|Little, John B (2006) Lauriston S. Taylor lecture: nontargeted effects of radiation: implications for low-dose exposures. Health Phys 91:416-26|
|Mamon, H J; Dahlberg, W; Azzam, E I et al. (2003) Differing effects of breast cancer 1, early onset (BRCA1) and ataxia-telangiectasia mutated (ATM) mutations on cellular responses to ionizing radiation. Int J Radiat Biol 79:817-29|
|Azzam, Edouard I; Nagasawa, Hatsumi; Yu, Yongjia et al. (2002) Cell cycle deregulation and xeroderma pigmentosum group C cell transformation. J Invest Dermatol 119:1350-4|
|Fitzek, Markus M; Dahlberg, William K; Nagasawa, Hatsumi et al. (2002) Unexpected sensitivity to radiation of fibroblasts from unaffected parents of children with hereditary retinoblastoma. Int J Cancer 99:764-8|
|Little, John B; Nagasawa, Hatsumi; Dahlberg, William K et al. (2002) Differing responses of Nijmegen breakage syndrome and ataxia telangiectasia cells to ionizing radiation. Radiat Res 158:319-26|
|Romney, C A; Paulauskis, J D; Nagasawa, H et al. (2001) Multiple manifestations of X-ray-induced genomic instability in Chinese hamster ovary (CHO) cells. Mol Carcinog 32:118-27|
|Syljuasen, R G; Krolewski, B; Little, J B (2001) Molecular events in radiation transformation. Radiat Res 155:215-221|
|Romney, C A; Paulauskis, J D; Little, J B (2001) X-ray induction of microsatellite instability at autosomal loci in human lymphoblastoid WTK1 cells. Mutat Res 478:97-106|
|Krolewski, B; Little, J B (2000) Overexpression of p21 protein in radiation-transformed mouse 10T(1/2) cell clones. Mol Carcinog 27:141-8|
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