Document Detail

An anti-sense construct of full-length ATM cDNA imposes a radiosensitive phenotype on normal cells.
MedLine Citation:
PMID:  9779997     Owner:  NLM     Status:  MEDLINE    
The cloning of a full-length cDNA for the gene (ATM) mutated in the human genetic disorder ataxia-telangiectasia (A-T) has been described recently. This cDNA, as well as a fragment representing a functional region from ATM, are capable of rescuing various aspects of the radiosensitive phenotype in A-T cells. We have subcloned full-length ATM cDNA in the opposite orientation in an EBV-based vector under the control of an inducible promoter to determine whether this anti-sense construct might sensitize control lymphoblastoid cells to ionizing radiation. The effectiveness of expression of this construct in control cells was monitored by loss of ATM protein which was evident over a period 6-12 h after induction. Under these conditions radiosensitivity was enhanced approximately threefold in control cells, approaching the degree of radiosensitivity observed in A-T cells. Expression of the anti-sense construct also increased the number of radiation-induced chromosomal breaks and led to the appearance of radioresistant DNA synthesis in these cells. Abrogation of the G1/S checkpoint was evident from the loss of the p53 response and that of its downstream effector, p21/WAF1, post-irradiation. The extent of accumulation of transfected cells in G2/M phase at 24 h post-irradiation was similar to that observed in A-T cells and the induction of stress-activated protein kinase by ionizing radiation was prevented by antisense ATM cDNA expression. These data demonstrate that full-length ATM anti-sense cDNA, by reducing the amount of ATM protein, is effective in imposing a series of known defects characteristic of the A-T phenotype. This inducible system provides an experimental model to further investigate mechanisms underlying radiosensitivity and cell cycle control.
N Zhang; P Chen; M Gatei; S Scott; K K Khanna; M F Lavin
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Oncogene     Volume:  17     ISSN:  0950-9232     ISO Abbreviation:  Oncogene     Publication Date:  1998 Aug 
Date Detail:
Created Date:  1998-11-23     Completed Date:  1998-11-23     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  811-8     Citation Subset:  IM    
Queensland Cancer Fund Research Laboratories, Brisbane, Australia.
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MeSH Terms
Ataxia Telangiectasia / genetics*
Cadmium Chloride / pharmacology
Calcium-Calmodulin-Dependent Protein Kinases / metabolism
Cell Cycle / drug effects,  physiology*,  radiation effects
Cell Cycle Proteins
Cell Division
Cell Line
Cell Survival / drug effects,  radiation effects
Chromosome Aberrations*
Cloning, Molecular
DNA / biosynthesis
DNA, Antisense*
DNA-Binding Proteins
Gamma Rays
JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinases*
Polymerase Chain Reaction
Protein Biosynthesis
Protein-Serine-Threonine Kinases*
Proteins / genetics*
Radiation Tolerance / genetics*
Recombinant Proteins / biosynthesis
Restriction Mapping
Tumor Suppressor Proteins
Reg. No./Substance:
0/Cell Cycle Proteins; 0/DNA, Antisense; 0/DNA-Binding Proteins; 0/Proteins; 0/Recombinant Proteins; 0/Tumor Suppressor Proteins; 10108-64-2/Cadmium Chloride; 9007-49-2/DNA; EC Kinases; EC telangiectasia mutated protein; EC Protein Kinases; EC Mitogen-Activated Protein Kinases; EC Protein Kinases

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