Transcriptional downregulation of ATM by EGF is defective in ataxia-telangiectasia cells expressing mutant protein

Keating, Katherine E., Gueven, Nuri, Watters, Dianne, Rodemann, H. Peter and Lavin, Martin F. (2001) Transcriptional downregulation of ATM by EGF is defective in ataxia-telangiectasia cells expressing mutant protein. Oncogene, 20 32: 4281-4290. doi:10.1038/sj.onc.1204527


Author Keating, Katherine E.
Gueven, Nuri
Watters, Dianne
Rodemann, H. Peter
Lavin, Martin F.
Title Transcriptional downregulation of ATM by EGF is defective in ataxia-telangiectasia cells expressing mutant protein
Journal name Oncogene   Check publisher's open access policy
ISSN 0950-9232
Publication date 2001-07-19
Sub-type Article (original research)
DOI 10.1038/sj.onc.1204527
Volume 20
Issue 32
Start page 4281
End page 4290
Total pages 10
Place of publication Basingstoke UK
Publisher Nature Publishing Group
Collection year 2001
Language eng
Subject C1
730108 Cancer and related disorders
270199 Biochemistry and Cell Biology not elsewhere classified
Abstract There is evidence that ATM plays a wider role in intracellular signalling in addition to DNA damage recognition and cell cycle control, In this report we show that activation of the EGF receptor is defective in ataxia-telangiectasia (A-T) cells and that sustained stimulation of cells with EGF downregulates ATM protein in control cells but not in A-T cells expressing mutant protein, Concomitant with the downregulation of ATM, DNA-binding activity of the transcription factor Spl decreased in controls after EGF treatment but increased from a lower basal level in A-T cells to that in untreated control cells, Mutation in two Spl consensus sequences in the ATM promoter reduced markedly the capacity of the promoter to support luciferase activity in a reporter assay. Overexpression of anti-sense ATM cDNA in control cells decreased the;basal level of Spl, which in turn was increased by subsequent treatment of cells with EGF, similar to that observed in,A-T cells. On the other hand full-length ATM cDNA increased the basal level of Spl binding in A-T cells, and in response to EGF Spl binding decreased, confirming that this is an ATR I-dependent process. Contrary to that observed in control cells there was no radiation-induced change in ATM protein in EGF-treated A-T cells and likewise no alteration in Spl binding activity. The results demonstrate that EGF-induced downregulation of ATM (mutant) protein in A-T cells is defective and this appears to be due to less efficient EGFR activation and abnormal Spl regulation.
Keyword Biochemistry & Molecular Biology
Oncology
Cell Biology
Genetics & Heredity
Ataxia-telangiectasia Atm
Transcriptional Downregulation
Egf
Sp1 Transcriptional Factor
Epidermal Growth-factor
Damage-induced Phosphorylation
Cycle Checkpoint Pathway
Double-strand Breaks
Dna-damage
Gene-product
Dependent Phosphorylation
Ionizing-radiation
Sp1-mediated Transcription
Signal-transduction
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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Created: Wed, 15 Aug 2007, 01:53:14 EST