Site-directed mutagenesis of the ATM promoter: Consequences for response to proliferation and ionizing radiation

Gueven, Nuri, Keating, Karen, Fukao, Toshiyuki, Loeffler, Heidi, Kondo, Naomi, Rodemann, H. Peter and Lavin, Martin F. (2003) Site-directed mutagenesis of the ATM promoter: Consequences for response to proliferation and ionizing radiation. Genes Chromosomes & Cancer, 38 2: 157-167. doi:10.1002/gcc.10261


Author Gueven, Nuri
Keating, Karen
Fukao, Toshiyuki
Loeffler, Heidi
Kondo, Naomi
Rodemann, H. Peter
Lavin, Martin F.
Title Site-directed mutagenesis of the ATM promoter: Consequences for response to proliferation and ionizing radiation
Journal name Genes Chromosomes & Cancer   Check publisher's open access policy
ISSN 1045-2257
Publication date 2003-01-01
Sub-type Article (original research)
DOI 10.1002/gcc.10261
Volume 38
Issue 2
Start page 157
End page 167
Total pages 11
Editor F. Mitelman
J.D. Rowley
Place of publication Hoboken, U.S.A.
Publisher John Wiley & Sons
Language eng
Subject C1
320305 Medical Biochemistry - Proteins and Peptides
730107 Inherited diseases (incl. gene therapy)
Abstract Although ATM, the protein defective in ataxia-telangiectasia (A-T), is activated primarily by radiation, there is also evidence that expression of the protein can be regulated by both radiation and growth factors. Computer analysis of the ATM promoter proximal 700-bp sequence reveals a number of potentially important cis-regulatory sequences. Using nucleotide substitutions to delete putative functional elements in the promoter of ATM, we examined the importance of some of these sites for both the basal and the radiation-induced activity of the promoter. In lymphoblastoid cells, most of the mutations in transcription factor consensus sequences [Sp1(1), Sp1(2), Cre, Ets, Xre, gammaIre(2), a modified AP1 site (Fse), and GCF] reduced basal activity to various extents, whereas others [gammaIre(1), NF1, Myb] left basal activity unaffected. In human skin fibroblasts, results were generally the same, but the basal activity varied up to 8-fold in these and other cell lines. Radiation activated the promoter approximately 2.5-fold in serum-starved lymphoblastoid cells, reaching a maximum by 3 hr, and all mutated elements equally blocked this activation. Reduction in Sp1 and AP1 DNA binding activity by serum starvation was rapidly reversed by exposure of cells to radiation. This reduction was not evident in A-T cells, and the response to radiation was less marked. Data provided for interaction between ATM and Sp1 by protein binding and co-immunoprecipitation could explain the altered regulation of Sp1 in A-T cells. The data described here provide additional evidence that basal and radiation-induced regulation of the ATM promoter is under multifactorial control. (C) 2003 Wiley-Liss, Inc.
Keyword Oncology
Genetics & Heredity
Ataxia-telangiectasia Fibroblasts
Tyrosine-hydroxylase Gene
Nf-kappa-b
Transcription Factors
Up-regulation
Wild-type
C-jun
Protein
Cells
Activation
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
2004 Higher Education Research Data Collection
School of Medicine Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 25 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 25 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Wed, 15 Aug 2007, 11:25:24 EST