Defective radiation signal transduction in ataxia-telangiectasia cells

Yan, J., Khanna, K. K. and Lavin, M. F. (2000) Defective radiation signal transduction in ataxia-telangiectasia cells. International Journal of Radiation Biology, 76 8: 1025-1035. doi:10.1080/09553000050111497


Author Yan, J.
Khanna, K. K.
Lavin, M. F.
Title Defective radiation signal transduction in ataxia-telangiectasia cells
Journal name International Journal of Radiation Biology   Check publisher's open access policy
ISSN 0955-3002
Publication date 2000-01-01
Sub-type Article (original research)
DOI 10.1080/09553000050111497
Volume 76
Issue 8
Start page 1025
End page 1035
Total pages 11
Place of publication London, U.K.
Publisher Taylor & Francis
Collection year 2000
Language eng
Subject C1
321015 Oncology and Carcinogenesis
321023 Radiotherapy and Nuclear Medicine
730108 Cancer and related disorders
Abstract Purpose: The product of the gene ATM mutated in the human genetic disorder ataxia-telangiectasia (A-T) is predominantly present, in the nucleus compatible with a role in DNA-damage recognition and cell-cycle control. However, ATM is also present outside the nucleus in cytoplasmic and membrane associated vesicles, which may explain the more general signalling defect in A-T. This led us to investigate signalling events initiated by ionizing radiation, remote from the nucleus. Materials and Methods: A-T and control lymphoblastoid cells were employed to study radiation-induced signalling at the level of protein activation using immunoprecipitation and immunoblotting. Flow cytometry was used to determine mobilization of intracellular Ca2+ Results: Lymphoblastoid cells from A-T patients were found to be defective in the radiation-induced activation of protein tyrosine kinase p53/p56(lyn). In control cells Ca2+ was mobilized in response to gamma-radiation largely from internal stores, and increased significantly over a 20 min period. This mobilization of Ca2+ was either absent or increased very slowly in A-T cells post-irradiation. The same pattern of release was observed after treatment with the radiometric agent, streptonigrin. In addition the phospatidylinositol 3-kinase (PI3-kinase) inhibitor wortmannin suppressed the release of Ca2+ Conclusion: These data demonstrate that ionizing radiation activates lyn kinase and leads to the release of Ca2+, and-for the first time-that these steps are ATM-dependent.
Keyword Biology
Nuclear Science & Technology
Radiology, Nuclear Medicine & Medical Imaging
Squamous Carcinoma-cells
Cycle Checkpoint Pathway
Dependent Protein-kinase
Lymphocyte-b Precursors
Double-strand Breaks
Abl Tyrosine Kinase
Ionizing-radiation
Gene-product
Atm Protein
Dna-damage
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Centre for Clinical Research Publications
 
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Created: Tue, 10 Jun 2008, 20:30:30 EST