Nitric Oxide–Induced Apoptosis in Lymphoblastoid and Fibroblast Cells Dependent on the Phosphorylation and Activation of p53

McLaughlin, Laura M.; Demple, Bruce

doi:10.1158/0008-5472.can-04-4254

Cited by 32 publications

(25 citation statements)

References 48 publications

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“…Thus, the effect of caffeine on T cells may not be specific to inhibition of Atm. There has also been some controversy as to the effect of caffeine on Atm inhibition in cells (31), although several studies support the use of caffeine as an inhibitor of Atm in vivo (32)(33)(34)(35)(36)(37)(38)(39). In addition, caffeine is metabolized through the xanthine oxidase pathway in vivo, which stimulates ROS production.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Oxidative Stress Responses by Ataxia-Telangiectasia Mutated Is Required for T Cell Proliferation

Bagley

Singh

Iacomini

2007

The Journal of Immunology

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Mutations in the gene encoding ataxia-telangiectasia (A-T) mutated (Atm) cause the disease A-T, characterized by immunodeficiency, the molecular basis of which is not known. Following stimulation through the TCR, Atm-deficient T cells and normal T cells in which Atm is inhibited undergo apoptosis rather than proliferation. Apoptosis is prevented by scavenging reactive oxygen species (ROS) during activation. Atm therefore plays a critical role in T cell proliferation by regulating responses to ROS generated following T cell activation. The inability of Atm-deficient T cells to control responses to ROS is therefore the molecular basis of immunodeficiency associated with A-T.

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Section: Discussionmentioning

confidence: 99%

Regulation of Oxidative Stress Responses by Ataxia-Telangiectasia Mutated Is Required for T Cell Proliferation

Bagley

Singh

Iacomini

2007

The Journal of Immunology

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“…Although nitric oxide is a known activator of p53 (30,31), we recently observed that the repair of nitric oxide-damaged DNA in ␤-cells occurs by a p53-independent but GADD45␣-dependent process (32). A number of studies have shown that GADD45␣ expression is regulated by p53 (33).…”

mentioning

confidence: 99%

FoxO1 and SIRT1 Regulate β-Cell Responses to Nitric Oxide

Hughes

Meares

Hansen

et al. 2011

Journal of Biological Chemistry

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For many cell types, including pancreatic ␤-cells, nitric oxide is a mediator of cell death; paradoxically, nitric oxide can also activate pathways that promote the repair of cellular damage. In this report, a role for FoxO1-dependent transcriptional activation and its regulation by SIRT1 in determining the cellular response to nitric oxide is provided. In response to nitric oxide, FoxO1 translocates from the cytoplasm to the nucleus and stimulates the expression of the DNA repair gene GADD45␣, resulting in FoxO1-dependent DNA repair. FoxO1-dependent gene expression appears to be regulated by the NAD ؉ -dependent deacetylase SIRT1. In response to SIRT1 inhibitors, the FoxO1-dependent protective actions of nitric oxide (GADD45␣ expression and DNA repair) are attenuated, and FoxO1 activates a proapoptotic program that includes PUMA (p53-up-regulated mediator of apoptosis) mRNA accumulation and caspase-3 cleavage. These findings support primary roles for FoxO1 and SIRT1 in regulating the cellular responses of ␤-cells to nitric oxide.Nitric oxide plays a central role in regulating the response(s) of pancreatic ␤-cells to cytokine treatment. Cytokines such as IL-1 (rat) and a combination of IL-1 ϩ IFN-␥ (mouse and human) stimulate the expression of the inducible isoform of nitric-oxide synthase (NOS) and the production of micromolar levels of nitric oxide by ␤-cells (1-4). Nitric oxide attenuates insulin secretion by inhibiting the oxidation of glucose to CO 2 and the activity of mitochondrial iron-sulfur center containing enzymes such as aconitase and complexes of the electron transport system (5, 6). The result is a 4-fold reduction in cellular ATP concentration (2, 7) that leads to the inhibition of glucose-induced insulin secretion due to the inability to generate sufficient levels of ATP to close the ATPsensitive K ϩ channels, an event required for ␤-cell depolarization and Ca 2ϩ -dependent exocytosis (8, 9). In addition to the inhibition of ␤-cell function, nitric oxide induces DNA strand breaks and oxidative DNA damage (10, 11).The inhibitory actions of IL-1 on ␤-cell function and DNA damage are reversible (12, 13). The addition of a NOS inhibitor to islets pretreated for 24 h with IL-1 (without removing IL-1) results in a time-dependent recovery of insulin secretion and mitochondrial function (3) and the repair of damaged DNA (14,15). This recovery response requires new gene expression, the activation of JNK, and can be stimulated by nitric oxide (16,17). The ability of ␤-cells to recover from cytokine-and nitric oxide-induced damage is temporally limited. Following a 36-h exposure to IL-1, ␤-cells are no longer capable of recovering metabolic and secretory function, and the islets are committed to death (14, 18). Studies have shown that cytokines can kill ␤-cells by nitric oxide-dependent and -independent necrotic and apoptotic mechanisms (19 -26). This dichotomy in the type of cell death that has been observed appears to reflect the temporal changes in the metabolic responses and the extent of DNA damage ca...

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“…When acting upon the cell cycle machinery, NO affects multiple pathways and can contribute to cell cycle arrest through several independent mechanisms (5, 8-10, 19, 20, 22). Several major regulators of the cell cycle and stress response, e.g., cyclin-dependent kinase 2 (cdk2), cdk inhibitor p21/WAF, cyclin D1, PCNA, ribonucleotide reductase, mdm2, p53, and ataxia telangectasia mutated kinase (ATM) are involved in the cellular response to NO (2,14,18,24,25). Given the extent of NO involvement in cell physiology, it is likely that specific additional components mediate the response to NO in particular contexts.…”

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confidence: 99%

noxin, a Novel Stress-Induced Gene Involved in Cell Cycle and Apoptosis

Nakaya

Hemish

Krasnov

et al. 2007

Molecular and Cellular Biology

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We describe a novel stress-induced gene, noxin, and a knockout mouse line with an inactivated noxin gene. The noxin gene does not have sequelogs in the genome and encodes a highly serine-rich protein with predicted phosphorylation sites for ATM, Akt, and DNA-dependent protein kinase kinases; nuclear localization signals; and a Zn finger domain. noxin mRNA and protein levels are under tight control by the cell cycle. noxin, identified as a nitric oxide-inducible gene, is strongly induced by a wide range of stress signals: ␥-and UV irradiation, hydrogen peroxide, adriamycin, and cytokines. This induction is dependent on p53. Noxin accumulates in the nucleus in response to stress and, when ectopically expressed, Noxin arrests the cell cycle at G 1 ; although it also induces p53, the cell cycle arrest function of Noxin is independent of p53 activity. noxin knockout mice are viable and fertile; however, they have an enlarged heart, several altered hematopoietic parameters, and a decreased number of spermatids. Importantly, loss or downregulation of Noxin leads to increased cell death. Our results suggest that Noxin may be a component of the cell defense system: it is activated by various stress stimuli, helps cells to withdraw from cycling, and opposes apoptosis.Cells respond to oxidative and genotoxic stress by withdrawing from the cell cycle, repairing the damaged regions of DNA, repairing or destroying affected proteins, altering growth characteristics, and seeking to inactivate the stressor. Alternatively, if the stress-induced damage is too extensive, cells may be eliminated by apoptosis. Various stressors (e.g., ionizing radiation, UV radiation, reactive oxygen and nitrogen species, and alkylating chemicals) act differently and cause distinct types of damage to the cell; at the same time, these dissimilar insults activate shared sets of molecules and pathways aimed at minimizing the damage and repairing the affected cell components (1,11,12,16). The cellular defense mechanisms include immediate responses (e.g., posttranslational modifications of the tumor suppressor protein p53, leading to its accumulation in the cells), as well as more extended responses (e.g., transcriptional activation of sets of crucial genes whose products help the cells to complete the repair process or to communicate the stress and repair signals to the surrounding cells). Together, this coordinated set of protein modification and gene activation events helps ensure that the damage to cells is minimized and that cells restore their prestress status (e.g., return to cycling).Nitric oxide (NO) is a versatile signaling molecule that is involved in both physiologic (e.g., vasorelaxation and neurotransmission) and pathological (e.g., inflammation and cell death) processes in the organism (3,15,19). When produced at high levels (e.g., by the high-output inducible NOS isoform), it can induce cell damage and subsequent apoptosis (4, 17). At lower levels, NO can act as an antiproliferative agent in vitro and in vivo, contributing to cell cycle ar...

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Nitric Oxide–Induced Apoptosis in Lymphoblastoid and Fibroblast Cells Dependent on the Phosphorylation and Activation of p53

Cited by 32 publications

References 48 publications

Regulation of Oxidative Stress Responses by Ataxia-Telangiectasia Mutated Is Required for T Cell Proliferation

Regulation of Oxidative Stress Responses by Ataxia-Telangiectasia Mutated Is Required for T Cell Proliferation

FoxO1 and SIRT1 Regulate β-Cell Responses to Nitric Oxide

noxin, a Novel Stress-Induced Gene Involved in Cell Cycle and Apoptosis

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