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Mutagenesis, Vol. 16, No. 5, 443-448, September 2001
© 2001 UK Environmental Mutagen Society/Oxford University Press

ATM status confers sensitivity to arsenic cytotoxic effects

D. Menéndez, G. Mora, A.M. Salazar and P. Ostrosky-Wegman,1

Instituto de Investigaciones Biomédicas, UNAM, Apartado Postal 70228, D.F., Mexico City 04510, México


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
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 P21WAF 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.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Under normal physiological conditions mammalian cells respond to DNA damage by inhibiting cell cycle progression, repairing DNA injury or, if the damage is beyond repair, inducing apoptosis. After exposure to DNA damaging agents the protein P53 plays an important role in accurate accomplishment of the cell cycle (Lane, 1992Go; Levine, 1997Go; Meek, 1998Go) and has been proposed to be `the universal damage sensor' (Lane, 1992Go).

P53 is activated by various exogenous and endogenous signals following DNA clastogenic injury and other cellular stress (Kastan et al.1991Go; Levine, 1997Go; Meek, 1998Go). Activation of P53 is generally triggered by a post-translational mechanism leading to stabilization of the otherwise normally rapidly degraded protein (Maltzman and Czyzyk, 1984Go), which modulates growth arrest in the G1/S, G2, G2/M and M cell cycle phases in order to prevent proliferation of genetically damaged cells (Lane, 1994Go; Schwartz and Rotter, 1997Go; Magnelli et al.1997Go; Levine, 1997Go).

The role of P53 in the regulation of cell proliferation and tumor suppression is a combination of signals, particularly in the control of cell cycle checkpoints and induction of apoptosis. P53 activity impairment or its aberrant expression contributes to cellular deregulation, transformation or cell death (Holt, 1992Go; Hamel and Hanley-Hyde, 1997Go).

The DNA damage-dependent signaling pathway that induces activation of p53 protein by DNA damaging agents is mediated by the ATM gene (Kastan et al.1992Go; Schwartz and Rotter, 1997Go; Barlow et al.1997Go; Banin et al.1998Go; Waterman et al.1998Go). This gene encodes a nuclear phosphoprotein which is a member of the phosphatidylinositol 3-kinase family (Gatti et al.1988Go) and is responsible for ataxia telangiectasia (AT). AT is an autosomal recessive disorder with multiple clinical and biological abnormalities, including immune defects, premature aging and cancer susceptibility. AT cells show chromosome instability and are hypersensitive to killing by radiation (Boder, 1985Go; Gatti, 1998Go).

P53 activates several genes whose products mediate cell cycle arrest (Kastan et al.1991Go; Lane, 1992Go; Levine, 1997Go; Meek, 1998Go).The cyclin-dependent kinase inhibitor p21WAF is one of these, which plays an essential role in P53-dependent cell cycle arrest, particularly in the G1/S phase (El-Deiry et al.1993Go; Ko and Prives, 1996Go; El-Deiry, 1998Go).

Positive and negative regulators of cell proliferation (Germolec et al.1997Go; Trouba et al.2000Go) are altered by As, a known human carcinogen, suggesting that modulation of the expression of genes that regulate cell growth contributes to the carcinogenic effects of this metalloid. Different responses to As have been found and there are several reports suggesting the existence of individual susceptibility to As genotoxic effects (Gonsebatt et al.1992bGo,1994Go; Vega et al.1995Go).

Particularly in the case of P53, different in vivo and in vitro studies have established a relationship between As exposure and modification of p53 gene expression and functionality (Kuo et al.1997Go; Mass and Wang, 1997Go; Salazar et al.1997Go; Chang et al.1998Go). A recent report showed that sodium arsenite treatment did not induce P53 in human fibroblasts from AT patients (Yih and Lee, 2000Go). The present work has been designed to investigate the role that the ATM–P53 signal might play in sensitivity to As. We also evaluated the effects of As exposure on P21WAF protein expression, the main effector of P53 activity.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Cell lines and cultures
Blood samples were obtained from AT patients and obligate heterozygotes that had been previously genotyped and were donated to our laboratory by Dr R.Gatti. Samples were also taken from controls with no history of cancer. Lymphocytes were isolated on Ficoll–Hypaque gradients and subsequently transformed with Epstein–Barr virus (EBV) as previously described (Pelloquin et al.1986Go). Immortalized lymphoblastoid cell lines were maintained in RPMI 1640 with 10% fetal bovine serum at 37°C in 5% CO2. The cell lines used in this study were two normal cell lines (CHOC and LCL-1), six ATM heterozygous cell lines (ATH5LA, ATH7LA, ATH8LA, ATH9LA,ATH28LA and MHO) and six AT cell lines (AT11LA, L3, GMO8436, DGE, AT36LA and AT156LA).

Arsenic treatments
An aqueous sterile stock solution of sodium arsenite (10 mg/ml) (CAS no. 7784-46-5; Sigma) was prepared and an appropriate volume was diluted to obtain the desired final concentrations. After growth for 24 h, 1x106 cells/ml were incubated in medium with various concentrations of sodium arsenite (1, 5, 10 and 25 µM) for an additional period of 24 h.

Fluorescein diacetate (FDA) assay
Cell viability was determined after As treatment by the FDA assay as previously described (Hartmann and Speit, 1996Go). Briefly, after 24 h As treatment an aliquot of 800 µl of cell culture was taken and the cells were recovered by centrifugation, the pellet was resuspended and washed twice in 1x phosphate-buffered saline (PBS) and finally resuspended in 50 µl of PBS. To measure cell viability, the recovered cells were mixed 1:1 (v/v) with stain solution containing FDA and ethidium bromide in 1x PBS, dropped onto a slide and 500 cells were analyzed on a fluorescence microscope at 20x magnification.

P53 and P21 protein analysis
Analyses of P53, P21 and actin proteins were performed by western blotting, as described by Salazar et al. (1997). Briefly, cell pellets from control and As-treated cultures seeded at a final concentration of 5x106 cells were lysed in RIPA buffer. Aliquots of 30 µg total protein were separated by 4–12% SDS–PAGE and transferred to nitrocellulose membranes. Cellular levels of P53, P21 and actin were detected by immunoblotting with anti-P53, anti-actin and anti-P21 antibodies (Santa Cruz) using horseradish peroxidase-coupled IgG as secondary antibody (Santa Cruz). The immunoreactive bands on autoradiographic films were visualized by ECL (Amersham, Tokyo, Japan). The relative intensity of the bands was quantified by optical densitometry using Quantity One software (Bio-Rad). Actinomicyn D (AMD) (CAS no. 5076-0; Sigma) was used as a positive control.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
In order to evaluate cell viability after As treatment we used the FDA assay, which evaluates both membrane integrity and lysosomal metabolic activity (Hartmann and Speit, 1996Go). Exposure of normal, ATM heterozygous and ATM homozygous (AT cells) lymphoblastoid cell lines to sodium arsenite for 24 h showed dose-dependent cytotoxicity in the cell lines tested. Figure 1Go shows the average of two normal cell lines, six ATM heterozygous cell lines and six AT cell lines. The ATM heterozygous and AT cell lines were statistically (P < 0.001, ANOVA) more sensitive to As than the normal lymphoblastoid cell line. These differences were observed with 1 and 5 µM sodium arsenite; doses of 10 and 25 µM were highly cytotoxic. The latter induced 80% cell death in the ATM heterozygous and homozygous cells and 40% in normal cell lines. Interestingly, heterozygous cell lines appeared to be statistically more sensitive to As treatment than homozygous cell lines (P < 0.01).



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  		Fig. 1. . Effect of sodium arsenite in normal and ATM heterozygous and homozygous cell lines. Cell cultures were treated with different doses of As for 24 h. Cell viability was evaluated by FDA assay as described in Materials and methods. Each point represents the average of two normal cell lines, six ATM heterozygous cell lines and six AT cell lines. Six independent experiments for each cell line by allelic condition were carried out. *P < 0.001, ANOVA with respect to normal cell lines; °P < 0.01, ANOVA, ATM heterozygous cell lines with respect to AT cell lines.

 
Trying to understand the different sensitivities to As conferred by ATM gene status, we investigated induction of P53 by treating our model cell system for 24 h with different doses of sodium arsenite. In normal and ATM heterozygous cell lines (Figure 2A and BGo, respectively) we observed a dose-dependent induction of P53, while in the AT cell lines the band corresponding to P53 was very weak or did not appear (Figure 2CGo). However, the protein inhibitor AMD, used as a positive control, significantly induced P53 in all cell lines, including the AT cells.





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  		Fig. 2. . P53 and P21 responses induced by sodium arsenite treatment for 24 h in (A) normal, (B) ATM heterozygous and (C) AT cell lines. It shows the representative blot of three independent experiments. As an internal control we used the housekeeping protein actin.

 
Figure 3Go shows densitometric analysis of the bands obtained from the western blots. In the normal and ATM heterozygous cell lines maximal induction of P53 was observed after exposure to 10 µM sodium arsenite. The P53 response was statistically higher (P < 0.05) than the control, beginning at 5 µM sodium arsenite, in both the normal and ATM heterozygous cell lines, except in cell line ATH9LA, which presented a very low P53 signal.




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  		Fig. 3. . Densitometric analysis of (A) P53 and (B) P21 responses in normal, ATM heterozygous and AT lymphoblastoid cell lines treated with As for 24 h. AMD was used as a positive control. Each bar represents the average of three independent experiments. *P < 0.05, ANOVA.

 
In the ATM heterozygous cell lines dose-dependent induction of P53 was observed, although the magnitude of this response was different among cell lines. P53 was not induced in any of the AT cell lines. It should be noted that all cell lines tested showed induction of P53 when treated with AMD, although differences in the amount of induced P53 were observed (Figure 3AGo).

To analyze the functionality of P53 we measured levels of P21WAF1, finding dose-dependent induction of P21WAF1 in normal cell lines, reaching a maximum at 10 µM As treatment (Figure 2AGo). Although the ATM heterozygous cell lines showed dose-dependent induction of P21, the magnitude of this response was lower than in normal cell lines (Figure 2BGo), while in the AT cell lines AT11LA and L3 no response was detected after As treatment (Figure 2CGo). Densitometric analyses of the P21WAF1 response are shown in Figure 3BGo. Induction with 5 and 10 µM As was statistically significant (P < 0.05) for normal and heterozygous cell lines.


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
ATM status confers sensitivity to As cytotoxic effects. Paradoxically cells heterozygous for ATM were more sensitive to As cytotoxic effects than ATM homozygous cells from AT patients.

The damage–stress signaling produced by sodium arsenite treatment results in induction of P53 protein dependent on the presence and functionality of ATM protein. The tumor suppressive function of P53 is linked to its ability to function as a sequence-specific transcriptional activator of a number of genes, including p21WAF1, which encodes P21WAF1, a CDK inhibitor that plays an essential role in the P53-dependent cell cycle arrest (El-Deiry et al.1993Go; Ko and Prives, 1996Go; El-Deiry, 1998Go). In AT cells As treatment did not induce P21 protein, while in normal and ATM carrier cell lines As induced a dose-dependent increase in P21 protein levels, similar to those observed for P53.

Thus, our results show that As induces an increase in P53 protein through the ATM cascade, activating P21WAF1. Since As is known to induce single-strand breaks (Hossain et al.2000Go; Ishitsuka et al.2000Go; Sordo et al., 2001Go), sister chormatid exchange, micronuclei, chromosomal aberrations (Gonsebatt et al.1992aGo,1997Go) and microtubule disruption (Ramírez et al.1997Go) among other effects (Snow, 1992Go; Aberhanty et al.1999Go), we propose that one or several of these effects is able to activate ATM. Once activated, ATM will turn on several substrates, including P53, which will induce the cyclin- dependent kinase inhibitor P21WAF1, that will, in turn, arrest the cell cycle in order to repair damage or induce elimination of damaged cells by apoptosis (Figure 4AGo). Therefore, the higher sensitivity of the ATM heterozygous cell lines to As cytotoxic effects could be due to activation of apoptosis and removal of non-repairable cells. In contrast, in AT cells, in which ATM is absent or mutated (Figure 4BGo), 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.




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  		Fig. 4. . Model of arsenic induction of the signaling cascade of P53 and P21: (A) with functional ATM; (B) with mutated or non-functional ATM. For details see text.

 
The different sensitivities to As observed among the ATM heterozygous cell lines could be explained if they carry a different type of mutation. Gatti et al. (1999) proposed that two distinct groups of ATM mutations may exist: one leading to truncated ATM protein and another with missense ATM mutations. According to this hypothesis, heterozygotes with truncating ATM mutations express predominantly wild-type ATM, whereas heterozygotes with missense mutations express mutant ATM protein, which probably results in a phenotype more like a homozygous null. Those heterozygous cell lines that showed a greater sensitivity to As could be those with the missense genotype, although the relationship between specific ATM mutations and As effects on viability and P53 induction still needs to be established.

It should be pointed out that ATM carriers do not show any of the major symptoms and cellular defects of the disease and that cell lines from such individuals have an underlying cellular radiosensitivity compared with normal cells, although not to the extent seen in AT patients cells (Halazonetis and Shiloh, 1999Go). It has been proposed that since homozygous loss of ATM leads to genetic instability, the cellular sensitivity of ATM heterozygotes suggests that haploinsufficiency for ATM may also promote oncogenesis. Although there is controversy, some epidemiological studies have shown that ATM heterozygotes have an increased tendency for development of cancer, particularly breast cancer (Atham et al.1996Go; Angele and Hall, 2000Go). The observation that ATM heterozygous lymphoblasts are more sensitive to As than either AT or normal cells could have a large impact on understanding which populations are at greatest risk following exposure to xenobiotics, particularly following As exposure, since the incidence of ATM carriers in the human population is substantially higher than AT patients.


   Acknowledgments
 
We are grateful to Drs Richard Gatti and Mike Shelby for their continuous support and revision of this manuscript, Dr L.A.Herrera for helpful comments and QFB M.Sordo for technical assistance. This project was partially supported by CONACYT and DGPA (UNAM).


   Notes
 
1 To whom correspondence should be addressed. Tel: +52 5 6223846; Fax: +52 5 6223365; Email: ostrosky{at}servidor.unam.mx Back


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Received on January 15, 2001; revised on April 20, 2001; accepted on May 24, 2001.


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