Ataxia-telangiectasia: chronic activation of damage-responsive functions is reduced by alpha-lipoic acid.
Cells from patients with the genetic disorder ataxia-telangiectasia (A-T) are hypersensitive to ionizing radiation and radiomimetic agents, both of which generate reactive oxygen species capable of causing oxidative damage to DNA and other macromolecules. We describe in A-T cells constitutive activation of pathways that normally respond to genotoxic stress. Basal levels of p53 and p21(WAF1/CIP1), phosphorylation on serine 15 of p53, and the Tyr15-phosphorylated form of cdc2 are chronically elevated in these cells. Treatment of A-T cells with the antioxidant alpha-lipoic acid significantly reduced the levels of these proteins, pointing to the involvement of reactive oxygen species in their chronic activation. These findings suggest that the absence of functional ATM results in a mild but continuous state of oxidative stress, which could account for several features of the pleiotropic phenotype of A-T.
Gatei
M
M
Queensland Cancer Fund Research Laboratories, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Herston, Brisbane, Qld, 4029, Australia.
Shkedy
D
D
Khanna
K K
KK
Uziel
T
T
Shiloh
Y
Y
Pandita
T K
TK
Lavin
M F
MF
Rotman
G
G
D000975:Antioxidants / Q000494:pharmacology*; D001260:Ataxia Telangiectasia / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016203:CDC2 Protein Kinase / Q000187:drug effects / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000187:drug effects / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D006801:Humans; D018384:Oxidative Stress; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D000975:Antioxidants; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D014443:Tyrosine; D008063:Thioctic Acid; D003513:Cycloheximide; D016203:CDC2 Protein Kinase