ATM status confers sensitivity to arsenic cytotoxic effects.
Arsenic (As), a human carcinogen, represents a worldwide health problem due to the high number of people exposed to this element in their drinking water. Previously our group has demonstrated that As can impair lymphocyte cell proliferation in vitro and in vivo and can increase the level of P53 protein, with different responses to these effects between individuals. Recently it has been shown that ATM protein, responsible for the autosomal recessive disorder ataxia telangiectasia (AT), regulates P53. In this study the induced response of P53 was evaluated following exposure to As in human lymphoblastoid cell lines normal (+/+), heterozygous (+/-) or homozygous (-/-) for the mutant ATM gene. After 24 h As treatment we found a dose-dependent induction of P53 in normal and heterozygous cell lines, although differences between cell lines were observed. An increase in P21(WAF) protein, a main effector of P53 activation, was also observed in the same cell lines. In contrast, neither P53 nor P21 induction was detected in homozygous cells. The ATM (+/-) and (-/-) genotypes confer more sensitivity to As cytotoxic effects than the normal allelic condition. Paradoxically, ATM heterozygous cells were more sensitive to As, leading us to propose that this might be related to activation of apoptosis and removal of non-repairable cells. In contrast, in AT cells in which ATM is absent or mutated activation of P53 and its target genes is abrogated, allowing cells to replicate with damage in the presence of As, with cell death ensuing by a pathway different from P53.
Menéndez
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Instituto de Investigaciones Biomédicas, UNAM, Apartado Postal 70228, D.F., Mexico City 04510, México.
Mora
G
G
Salazar
A M
AM
Ostrosky-Wegman
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P
D001151:Arsenic / Q000633:toxicity*; D001260:Ataxia Telangiectasia / Q000235:genetics / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins; D002273:Carcinogens / Q000633:toxicity*; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D004268:DNA-Binding Proteins; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology; D025521:Tumor Suppressor Proteins
C493956:CDKN1A protein, human; D002273:Carcinogens; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D001151:Arsenic