Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53

Li, Chun-Qi; Trudel, Laura J.; Wogan, Gerald N.

doi:10.1073/pnas.162356399

Cited by 74 publications

(95 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because p53 is a transcription factor regulating the expression of several genes involved in DNA repair, cell cycle arrest, and apoptosis, activation of p53 by NO can be considered as a regulatory mechanism preventing the emergence of NO-induced DNA mutations and, hence, tumorigenesis. Augmentation of mutation rates in p53-deficient cells exposed to high NO doses and repression of iNOS gene transcription by p53 in a negative feedback loop are occurrences that strongly support a major role for p53 in the control of NO-induced genotoxicity (7)(8)(9).…”

mentioning

confidence: 65%

TAp73 Induction by Nitric Oxide

Tebbi

Guittet

Cottet

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Nitric oxide (NO) is a potent activator of the p53 tumor suppressor protein, thereby inducing cell cycle arrest and apoptosis. However, little is known about the regulation of the two other p53-family members, p63 and p73, by nitrogen oxides. We report here an up-regulation of p73 by NO in p53-null K-562 leukemia cells. Chemical NO prodrugs or macrophage iNOS activity induced an accumulation of the TAp73␣ isoform in these cells, whereas macrophages from iNOS ؊/؊ mice did not. NO is a free radical implicated in numerous physiological functions. In cancer biology, both positive and negative actions of NO have been reported. For example, NO was found to promote tumor growth angiogenesis, and metastasis on the one hand and to induce apoptotic cell death or tumor cytostasis on the other hand (1-4). These opposite responses are linked to the chemistry of nitric oxide in a cellular context. NO not only reacts directly on target molecules but also exerts its effects through derived species with a higher degree of oxidation and generated from NO interaction with O 2 (e.g. N 2 O 3 , ⅐ NO 2 ) or superoxide anion (ONOO Ϫ ). Those reactive nitrogen species can act as potent nitrosating, nitrating, or oxidizing agents. Given this complex chemistry, the biological outcome of NO is directed by its concentration, the cellular redox environment, and different target susceptibilities. High fluxes of NO are generated by inducible NO synthase (iNOS), 3 transcriptionally induced in immune cells such as macrophages by cytokines and bacterial products (e.g. IFN-␥ and lipopolysaccharide). Elevated concentrations of NO cause DNA damage, mutation, and apoptotic cell death (5, 6). The tumor suppressor protein p53 is a key player in the DNA damage response and the onset of apoptosis. NO has been shown to activate p53 at high concentrations, which also promote genotoxic and pro-apoptotic effects (3, 6, 7). Because p53 is a transcription factor regulating the expression of several genes involved in DNA repair, cell cycle arrest, and apoptosis, activation of p53 by NO can be considered as a regulatory mechanism preventing the emergence of NO-induced DNA mutations and, hence, tumorigenesis. Augmentation of mutation rates in p53-deficient cells exposed to high NO doses and repression of iNOS gene transcription by p53 in a negative feedback loop are occurrences that strongly support a major role for p53 in the control of NO-induced genotoxicity (7-9). NO also up-regulatedTwo p53-related genes, p63 and p73, have been identified more than 15 years after the discovery of p53 (10, 11). The p53 family members have a similar structural organization comprising an NH 2 -terminal transactivation domain (TA), a central DNA binding domain, and a COOH-terminal oligomerization domain (12-15). In p63 and p73, an additional sterile-␣ motif and a transcription inhibitory domain may follow the oligomerization domain. Sequence homology among the three members is limited to 25-40% identity between TA and oligomerization domain regions but increases to 60 -80% amino...

show abstract

mentioning

confidence: 65%

TAp73 Induction by Nitric Oxide

Tebbi

Guittet

Cottet

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Low doses of NO can also be cytoprotective [21], mainly through a cGMP-mediated signaling mechanism [21,[25][26][27] or through caspase inhibition [28]. Elevated levels of NO can activate the p53 pathway [29] and induce apoptosis in some cell types [30,31]. Local immune hyperstimulation [32][33][34] is the major route through which neuronal cells are exposed to supraphysiological levels of reactive oxygen and nitrogen species including NO [35], and is thought to contribute to neurodegenerative conditions such as Parkinson's disease [36].…”

Section: Introductionmentioning

confidence: 99%

Nerve Growth Factor Potentiates p53 DNA Binding but Inhibits Nitric Oxide-Induced Apoptosis in Neuronal PC12 Cells

Brynczka

Merrick

2007

Neurochem Res

View full text Add to dashboard Cite

NGF is recognized for its role in neuronal differentiation and maintenance. Differentiation of PC12 cells by NGF involves p53, a transcription factor that controls growth arrest and apoptosis. We investigated NGF influence over p53 activity during NO-induced apoptosis by sodium nitroprusside in differentiated and mitotic PC12 cells. NGF-differentiation produced increased p53 levels, nuclear localization and sequence-specific DNA binding. Apoptosis in mitotic cells also produced these events but the accompanying activation of caspases 1-10 and mitochondrial depolarization were inhibited during NGF differentiation and could be reversed in p53-silenced cells. Transcriptional regulation of PUMA and survivin expression were not inhibited by NGF, although NO-induced mitochondrial depolarization was dependent upon de novo gene transcription and only occurred in mitotic cells. We conclude that NGF mediates prosurvival signaling by increasing factors such as Bcl-2 and p21 Waf1/Cip1 without altering p53 transcriptional activity and prevents mitochondrial depolarization and caspase activation to inhibit apoptosis.

show abstract

“…We showed previously that a high concentration of NO can inhibit p53 function by inducing conformational changes in p53. 8 Li et al 9 reported that NO-induced DNA damage and apoptosis depend on p53 status. In addition, it has been reported that transcription of iNOS can be downregulated by p53, 10,11 suggesting that functional loss of p53 protein, caused by mutation and/or loss of heterozygosity of the TP53 (human p53) gene, leads to overexpression of the iNOS gene.…”

mentioning

confidence: 99%

Suppression of thymic lymphomas and increased nonthymic lymphomagenesis in Trp53‐deficient mice lacking inducible nitric oxide synthase gene

Tatemichi

Tazawa

Masuda

et al. 2004

Intl Journal of Cancer

View full text Add to dashboard Cite

Trp53-deficient mice spontaneously develop lymphomas, mainly of thymic origin, although the molecular mechanism remains largely unknown. As several interaction effects between p53 and iNOS have been reported, we hypothesized that iNOS activity in the thymus is causally linked to lymphomagenesis in Trp53-deficient mice. We therefore created mouse strains with different combinations of the Trp53 and iNOS genes. Western blot and histologic analyses showed that the iNOS protein was constitutively expressed in the thymus independently of Trp53 status and its expression was enhanced in Trp53 ؉/-and Trp53 -/-mice compared to Trp53 ؉/؉ mice. Homozygous disruption of iNOS decreased the incidence of thymic lymphomas by almost 40% (p ‫؍‬ 0.087) and 90% (p < 0.05) in Trp53 -/-and Trp53 ؉/-mice, respectively, compared to the respective iNOS wild-type mice but significantly (p < 0.05) increased the development of nonthymic lymphomas in Trp53 -/-and Trp53 ؉/-mice. Although iNOS gene disruption did not affect the phenotype of thymic lymphomas, absence of the iNOS gene shifted the spectrum of nonthymic lymphoma from the B-cell to the T-cell lineage. RT-PCR analysis revealed enhanced expression of IL-10, which could have a promoting effect on lymphomagenesis, even without any stimulation, in the spleen of aging mice with the gene combinations Trp53 -/-iNOS -/-and Trp53 ؉/-iNOS -/-but not Trp53 -/-iNOS ؉/؉ or Trp53 ؉/-iNOS ؉/؉ . These results suggest that iNOS could increase the development of thymic lymphomas in Trp53-deficient mice. While iNOS may have protective effects against nonthymic lymphomagenesis, the regulation of cytokine production by iNOS may be involved in the underlying mechanism of antilymphomagenesis effects in the peripheral lymphoid organ.

show abstract

Nitric oxide-induced genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells expressing wild-type and mutant p53

Abstract: Nitric oxide (NO

Cited by 74 publications

References 43 publications

TAp73 Induction by Nitric Oxide

TAp73 Induction by Nitric Oxide

Nerve Growth Factor Potentiates p53 DNA Binding but Inhibits Nitric Oxide-Induced Apoptosis in Neuronal PC12 Cells

Suppression of thymic lymphomas and increased nonthymic lymphomagenesis in Trp53‐deficient mice lacking inducible nitric oxide synthase gene

Contact Info

Product

Resources

About