TY - JOUR
T1 - Impaired genomic stability and increased oxidative stress exacerbate different features of Ataxia-telangiectasia
AU - Ziv, Shelly
AU - Brenner, Ori
AU - Amariglio, Ninette
AU - Smorodinsky, Nechama I.
AU - Galron, Ronit
AU - Carrion, Danaise V.
AU - Zhang, Weijia
AU - Sharma, Girdhar G.
AU - Pandita, Raj K.
AU - Agarwal, Manjula
AU - Elkon, Ran
AU - Katzin, Nirit
AU - Bar-Am, Irit
AU - Pandita, Tej K.
AU - Kucherlapati, Raju
AU - Rechavi, Gideon
AU - Shiloh, Yosef
AU - Barzilai, Ari
N1 - Funding Information:
This work was supported by research grants from the A-T Children’s Project and the Israel Science Foundation to A.B. Work in the laboratory of Y.S. is supported by research grants from the A-T Medical Research Foundation, the A-T Children’s Project, the A-T Medical Research Trust, the National Institutes of Health (RO1 NS 31763) and the Israel Ministry of Science. We wish to thank the Arison family for their donation to the center of the DNA microarrays.
PY - 2005/10
Y1 - 2005/10
N2 - Ataxia-telangiectasia (A-T) is a multisystem, cancer-predisposing genetic disorder caused by deficiency of the ATM protein. To dissect the A-T phenotype, we augmented specific features of the human disease by generating mouse strains that combine Atm deficiency with dysfunction of other proteins. Increasing oxidative stress by combining deficiencies in Atm and superoxide dismutase 1 (Sod1) exacerbated growth retardation and markedly reduced the mean survival time following ionizing radiation. In contrast, increasing genomic instability by combining deficiencies of Atm and the mismatch repair protein Mlh1 caused a moderate increase in radiation sensitivity and dramatic increase in aggressive lymphomas, compared with thes Atm-/- single knockout. Remarkably, Atm, Mlh1 or Mlh1/ Atm single or double heterozygosity did not significantly affect the life span of the various genotypes. Mlh1/Atm double null tumors were polyclonal, whereas the tumors in other genotypes were mono- or oligoclonal, demonstrating the high predisposition of thymocytes with this genotype to become malignant. Chromosomal aberrations in the tumors were localized mainly in chromosomes 12 and 15. The genomic region on chromosome 15, which contains the gene for the c-Myc oncoprotein, was commonly amplified, and elevated levels of the c-Myc protein were subsequently observed in the tumors. Our data suggest that impaired genomic instability is an important contributing factor to cancer predisposition in A-T, whereas oxidative stress is more important in the radiation sensitivity and growth retardation facets of this disease.
AB - Ataxia-telangiectasia (A-T) is a multisystem, cancer-predisposing genetic disorder caused by deficiency of the ATM protein. To dissect the A-T phenotype, we augmented specific features of the human disease by generating mouse strains that combine Atm deficiency with dysfunction of other proteins. Increasing oxidative stress by combining deficiencies in Atm and superoxide dismutase 1 (Sod1) exacerbated growth retardation and markedly reduced the mean survival time following ionizing radiation. In contrast, increasing genomic instability by combining deficiencies of Atm and the mismatch repair protein Mlh1 caused a moderate increase in radiation sensitivity and dramatic increase in aggressive lymphomas, compared with thes Atm-/- single knockout. Remarkably, Atm, Mlh1 or Mlh1/ Atm single or double heterozygosity did not significantly affect the life span of the various genotypes. Mlh1/Atm double null tumors were polyclonal, whereas the tumors in other genotypes were mono- or oligoclonal, demonstrating the high predisposition of thymocytes with this genotype to become malignant. Chromosomal aberrations in the tumors were localized mainly in chromosomes 12 and 15. The genomic region on chromosome 15, which contains the gene for the c-Myc oncoprotein, was commonly amplified, and elevated levels of the c-Myc protein were subsequently observed in the tumors. Our data suggest that impaired genomic instability is an important contributing factor to cancer predisposition in A-T, whereas oxidative stress is more important in the radiation sensitivity and growth retardation facets of this disease.
UR - http://www.scopus.com/inward/record.url?scp=26444513273&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddi324
DO - 10.1093/hmg/ddi324
M3 - Article
C2 - 16150740
AN - SCOPUS:26444513273
SN - 0964-6906
VL - 14
SP - 2929
EP - 2943
JO - Human molecular genetics
JF - Human molecular genetics
IS - 19
ER -