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Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53
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| Zeitschriftentitel: | Proceedings of the National Academy of Sciences |
|---|---|
| Personen und Körperschaften: | , , |
| In: | Proceedings of the National Academy of Sciences, 99, 2002, 16, S. 10364-10369 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Proceedings of the National Academy of Sciences
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| Schlagwörter: |
| author_facet |
Li, Chun-Qi Trudel, Laura J. Wogan, Gerald N. Li, Chun-Qi Trudel, Laura J. Wogan, Gerald N. |
|---|---|
| author |
Li, Chun-Qi Trudel, Laura J. Wogan, Gerald N. |
| spellingShingle |
Li, Chun-Qi Trudel, Laura J. Wogan, Gerald N. Proceedings of the National Academy of Sciences Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53 Multidisciplinary |
| author_sort |
li, chun-qi |
| spelling |
Li, Chun-Qi Trudel, Laura J. Wogan, Gerald N. 0027-8424 1091-6490 Proceedings of the National Academy of Sciences Multidisciplinary http://dx.doi.org/10.1073/pnas.162356399 <jats:p> Nitric oxide (NO <jats:sup>•</jats:sup> ) is mutagenic and, under appropriate conditions of exposure, also induces apoptosis in many <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic> experimental models. Biochemical and cellular mechanisms through which NO <jats:sup>•</jats:sup> induces apoptosis are incompletely understood, but involve p53/mitochondria-dependent signaling pathways. In this study, we exposed human lymphoblastoid cells harboring either wild-type (TK6 cells) or mutant p53 (WTK-1 cells) to NO <jats:sup>•</jats:sup> , delivered by diffusion through Silastic tubing. Cells were exposed for 2 h at constant rates of 100–533 nM/s, similar to levels estimated to occur <jats:italic>in vivo</jats:italic> in inflamed tissues. DNA double-strand breaks and fragmentation detected 8–48 h after NO <jats:sup>•</jats:sup> treatment were more extensive in TK6 cells than in WTK-1 cells, whereas NO <jats:sup>•</jats:sup> -induced mutant fractions in both <jats:italic>HPRT</jats:italic> and <jats:italic>TK1</jats:italic> genes were significantly lower in TK6 cells than in WTK-1 cells ( <jats:italic>P</jats:italic> < 0.01–0.05) <jats:italic>.</jats:italic> Treatment of TK6 cells with NO <jats:sup>•</jats:sup> caused extensive apoptosis, but this response was delayed and greatly reduced in magnitude in WTK-1 cells. Mitochondrial membrane depolarization and cytochrome <jats:italic>c</jats:italic> release were induced in both cell types. However, elevation of apoptotic protease-activating factor-1 (Apaf-1) protein and reduction of X-chromosome-linked inhibitor of apoptosis (XIAP) protein were observed only in TK6 cells. These results indicate that p53 status is an important modulator of NO <jats:sup>•</jats:sup> -induced mutagenesis and apoptosis, and suggest that levels of the Apaf-1 and XIAP proteins, but not mitochondrial depolarization and cytochrome <jats:italic>c</jats:italic> release, are regulated by p53 in these human lymphoblastoid cells. Thus, Apaf-1 and XIAP may play important roles in the regulation of p53-mediated apoptotic responses. </jats:p> Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53 Proceedings of the National Academy of Sciences |
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Proceedings of the National Academy of Sciences, 2002 |
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Proceedings of the National Academy of Sciences, 2002 |
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0027-8424 1091-6490 |
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2002 |
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Proceedings of the National Academy of Sciences |
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| title |
Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53 |
| title_unstemmed |
Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53 |
| title_full |
Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53 |
| title_fullStr |
Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53 |
| title_full_unstemmed |
Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53 |
| title_short |
Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53 |
| title_sort |
nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53 |
| topic |
Multidisciplinary |
| url |
http://dx.doi.org/10.1073/pnas.162356399 |
| publishDate |
2002 |
| physical |
10364-10369 |
| description |
<jats:p>
Nitric oxide (NO
<jats:sup>•</jats:sup>
) is mutagenic and, under appropriate conditions of exposure, also induces apoptosis in many
<jats:italic>in vitro</jats:italic>
and
<jats:italic>in vivo</jats:italic>
experimental models. Biochemical and cellular mechanisms through which NO
<jats:sup>•</jats:sup>
induces apoptosis are incompletely understood, but involve p53/mitochondria-dependent signaling pathways. In this study, we exposed human lymphoblastoid cells harboring either wild-type (TK6 cells) or mutant p53 (WTK-1 cells) to NO
<jats:sup>•</jats:sup>
, delivered by diffusion through Silastic tubing. Cells were exposed for 2 h at constant rates of 100–533 nM/s, similar to levels estimated to occur
<jats:italic>in vivo</jats:italic>
in inflamed tissues. DNA double-strand breaks and fragmentation detected 8–48 h after NO
<jats:sup>•</jats:sup>
treatment were more extensive in TK6 cells than in WTK-1 cells, whereas NO
<jats:sup>•</jats:sup>
-induced mutant fractions in both
<jats:italic>HPRT</jats:italic>
and
<jats:italic>TK1</jats:italic>
genes were significantly lower in TK6 cells than in WTK-1 cells (
<jats:italic>P</jats:italic>
< 0.01–0.05)
<jats:italic>.</jats:italic>
Treatment of TK6 cells with NO
<jats:sup>•</jats:sup>
caused extensive apoptosis, but this response was delayed and greatly reduced in magnitude in WTK-1 cells. Mitochondrial membrane depolarization and cytochrome
<jats:italic>c</jats:italic>
release were induced in both cell types. However, elevation of apoptotic protease-activating factor-1 (Apaf-1) protein and reduction of X-chromosome-linked inhibitor of apoptosis (XIAP) protein were observed only in TK6 cells. These results indicate that p53 status is an important modulator of NO
<jats:sup>•</jats:sup>
-induced mutagenesis and apoptosis, and suggest that levels of the Apaf-1 and XIAP proteins, but not mitochondrial depolarization and cytochrome
<jats:italic>c</jats:italic>
release, are regulated by p53 in these human lymphoblastoid cells. Thus, Apaf-1 and XIAP may play important roles in the regulation of p53-mediated apoptotic responses.
</jats:p> |
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| author | Li, Chun-Qi, Trudel, Laura J., Wogan, Gerald N. |
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| description | <jats:p> Nitric oxide (NO <jats:sup>•</jats:sup> ) is mutagenic and, under appropriate conditions of exposure, also induces apoptosis in many <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic> experimental models. Biochemical and cellular mechanisms through which NO <jats:sup>•</jats:sup> induces apoptosis are incompletely understood, but involve p53/mitochondria-dependent signaling pathways. In this study, we exposed human lymphoblastoid cells harboring either wild-type (TK6 cells) or mutant p53 (WTK-1 cells) to NO <jats:sup>•</jats:sup> , delivered by diffusion through Silastic tubing. Cells were exposed for 2 h at constant rates of 100–533 nM/s, similar to levels estimated to occur <jats:italic>in vivo</jats:italic> in inflamed tissues. DNA double-strand breaks and fragmentation detected 8–48 h after NO <jats:sup>•</jats:sup> treatment were more extensive in TK6 cells than in WTK-1 cells, whereas NO <jats:sup>•</jats:sup> -induced mutant fractions in both <jats:italic>HPRT</jats:italic> and <jats:italic>TK1</jats:italic> genes were significantly lower in TK6 cells than in WTK-1 cells ( <jats:italic>P</jats:italic> < 0.01–0.05) <jats:italic>.</jats:italic> Treatment of TK6 cells with NO <jats:sup>•</jats:sup> caused extensive apoptosis, but this response was delayed and greatly reduced in magnitude in WTK-1 cells. Mitochondrial membrane depolarization and cytochrome <jats:italic>c</jats:italic> release were induced in both cell types. However, elevation of apoptotic protease-activating factor-1 (Apaf-1) protein and reduction of X-chromosome-linked inhibitor of apoptosis (XIAP) protein were observed only in TK6 cells. These results indicate that p53 status is an important modulator of NO <jats:sup>•</jats:sup> -induced mutagenesis and apoptosis, and suggest that levels of the Apaf-1 and XIAP proteins, but not mitochondrial depolarization and cytochrome <jats:italic>c</jats:italic> release, are regulated by p53 in these human lymphoblastoid cells. Thus, Apaf-1 and XIAP may play important roles in the regulation of p53-mediated apoptotic responses. </jats:p> |
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| imprint | Proceedings of the National Academy of Sciences, 2002 |
| imprint_str_mv | Proceedings of the National Academy of Sciences, 2002 |
| institution | DE-Ch1, DE-L229, DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161, DE-Zi4, DE-Gla1, DE-15, DE-Pl11, DE-Rs1, DE-14, DE-105 |
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| physical | 10364-10369 |
| publishDate | 2002 |
| publishDateSort | 2002 |
| publisher | Proceedings of the National Academy of Sciences |
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| series | Proceedings of the National Academy of Sciences |
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| spelling | Li, Chun-Qi Trudel, Laura J. Wogan, Gerald N. 0027-8424 1091-6490 Proceedings of the National Academy of Sciences Multidisciplinary http://dx.doi.org/10.1073/pnas.162356399 <jats:p> Nitric oxide (NO <jats:sup>•</jats:sup> ) is mutagenic and, under appropriate conditions of exposure, also induces apoptosis in many <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic> experimental models. Biochemical and cellular mechanisms through which NO <jats:sup>•</jats:sup> induces apoptosis are incompletely understood, but involve p53/mitochondria-dependent signaling pathways. In this study, we exposed human lymphoblastoid cells harboring either wild-type (TK6 cells) or mutant p53 (WTK-1 cells) to NO <jats:sup>•</jats:sup> , delivered by diffusion through Silastic tubing. Cells were exposed for 2 h at constant rates of 100–533 nM/s, similar to levels estimated to occur <jats:italic>in vivo</jats:italic> in inflamed tissues. DNA double-strand breaks and fragmentation detected 8–48 h after NO <jats:sup>•</jats:sup> treatment were more extensive in TK6 cells than in WTK-1 cells, whereas NO <jats:sup>•</jats:sup> -induced mutant fractions in both <jats:italic>HPRT</jats:italic> and <jats:italic>TK1</jats:italic> genes were significantly lower in TK6 cells than in WTK-1 cells ( <jats:italic>P</jats:italic> < 0.01–0.05) <jats:italic>.</jats:italic> Treatment of TK6 cells with NO <jats:sup>•</jats:sup> caused extensive apoptosis, but this response was delayed and greatly reduced in magnitude in WTK-1 cells. Mitochondrial membrane depolarization and cytochrome <jats:italic>c</jats:italic> release were induced in both cell types. However, elevation of apoptotic protease-activating factor-1 (Apaf-1) protein and reduction of X-chromosome-linked inhibitor of apoptosis (XIAP) protein were observed only in TK6 cells. These results indicate that p53 status is an important modulator of NO <jats:sup>•</jats:sup> -induced mutagenesis and apoptosis, and suggest that levels of the Apaf-1 and XIAP proteins, but not mitochondrial depolarization and cytochrome <jats:italic>c</jats:italic> release, are regulated by p53 in these human lymphoblastoid cells. Thus, Apaf-1 and XIAP may play important roles in the regulation of p53-mediated apoptotic responses. </jats:p> Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53 Proceedings of the National Academy of Sciences |
| spellingShingle | Li, Chun-Qi, Trudel, Laura J., Wogan, Gerald N., Proceedings of the National Academy of Sciences, Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53, Multidisciplinary |
| title | Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53 |
| title_full | Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53 |
| title_fullStr | Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53 |
| title_full_unstemmed | Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53 |
| title_short | Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53 |
| title_sort | nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53 |
| title_unstemmed | Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53 |
| topic | Multidisciplinary |
| url | http://dx.doi.org/10.1073/pnas.162356399 |