S-Nitrosylation of Bcl-2 Inhibits Its Ubiquitin-Proteasomal Degradation

Azad, Neelam; Vallyathan, Val; Wang, Liying; Tantishaiyakul, Vimon; Stehlik, Christian; Leonard, Stephen S.; Rojanasakul, Yon

doi:10.1074/jbc.m602551200

Cited by 183 publications

(141 citation statements)

References 59 publications

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“…Bcl-2 levels are controlled by its rate of synthesis, as well as by its rate of degradation by the ubiquitin-proteasomal pathway. Azad et al 116 have demonstrated that NO causes Snitrosylation of Bcl-2 in the human lung cancer cell line NIH-H460 and this prevents the ubiquitin-proteosomal degradation of Bcl-2, thus increasing its level and preventing Cr(VI)-mediated apoptosis of these cells. Bcl-2 Snitrosylation occurs on cys 158 and cys 229 of this protein and is mediated by either endogenous production of NO or by addition using external donors.…”

Section: Bcl-2 S-nitrosylation and Cancer Cell Apoptosismentioning

confidence: 99%

Nitric Oxide and Cancer Development

et al. 2007

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Abstract:The role of nitric oxide (NO) in cancer development has become a very active research area. This review presents an overview of many studies that implicate an important role of NO in the development of cancer. These include results in experimental models as well as many observations made on NO and inducible nitric oxide synthase (iNOS) in human cancers. Our survey of the literature has allowed us to conclude that in general large levels of NO will kill cancer cells but paradoxically at intermediate to lower levels NO prevents cancer cell apoptosis and enhances tumor growth. This basic tenet has been demonstrated in many experimental models. The mechanistic basis of how intermediate levels of NO mediate tumor development is an active area of research and is the subject of this review. NO mediated S-nitrosylation of key enzymes and regulatory proteins plays a critical role. Key proteins S-nitrosylated which enhance tumor development include several caspases involved in apoptosis, PTEN the tumor suppressor protein, Bcl-2 the mitochondrial protein which protects from apoptosis, OGG1 the DNA repair protein and methionine adenosyl transferase the liver protein which synthesizes adenosylmethionine. The S-nitrosylation of these proteins enhances DNA mutations, prevents cancer cell apoptosis and enhances oncogenic cell growth. (J Toxicol Pathol 2007; 20: 77-92)

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Section: Bcl-2 S-nitrosylation and Cancer Cell Apoptosismentioning

confidence: 99%

Nitric Oxide and Cancer Development

et al. 2007

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“…Dynamin also proved to be S-nitrosylated at C607 during endocytosis . On the other hand, NO also has anti-apoptotic function through S-nitrosylation of Bcl2, which inhibits ubiquitin-proteasomal degradation and thus inhibits apoptosis (Azad et al, 2006).…”

Section: Cell Death Signal Cascades Regulated By S-nitrosylationmentioning

confidence: 99%

Nitric oxide: promoter or suppressor of programmed cell death?

et al. 2010

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Nitric oxide (NO) is a short-lived gaseous free radical that predominantly functions as a messenger and effector molecule. It affects a variety of physiological processes, including programmed cell death (PCD) through cyclic guanosine monophosphate (cGMP)-dependent andindependent pathways. In this field, dominant discoveries are the diverse apoptosis networks in mammalian cells, which involve signals primarily via death receptors (extrinsic pathway) or the mitochondria (intrinsic pathway) that recruit caspases as effector molecules. In plants, PCD shares some similarities with animal cells, but NO is involved in PCD induction via interacting with pathways of phytohormones. NO has both promoting and suppressing effects on cell death, depending on a variety of factors, such as cell type, cellular redox status, and the flux and dose of local NO. In this article, we focus on how NO regulates the apoptotic signal cascade through protein S-nitrosylation and review the recent progress on mechanisms of PCD in both mammalian and plant cells.

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“…S-nitrosylation of Bcl-2 was measured as previously described (15). In brief, cells were treated, harvested, lysed, and subjected to immunoprecipitation as described previously here.…”

Section: Measurement Of Bcl-2 S-nitrosylationmentioning

confidence: 99%

Nitric Oxide–Mediated Bcl-2 Stabilization Potentiates Malignant Transformation of Human Lung Epithelial Cells

Azad¹,

Iyer²,

Wang³

et al. 2010

Am J Respir Cell Mol Biol

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Hexavalent chromium (Cr(VI)) compounds are known human carcinogens associated with the incidence of lung cancer. Although a direct correlation between Cr(VI) exposure and lung cancer has been established, several studies aimed at generating animal models for Cr(VI) have yielded inconsistent data that do not affirmatively support findings from epidemiologic studies. Because the lack of a good animal model has hindered the identification of molecular mechanisms involved in Cr(VI) exposure, we developed an in vitro model that facilitates mechanistic studies of Cr(VI)-induced carcinogenesis. We report here that long-term exposure to Cr(VI) leads to the malignant transformation of nontumorigenic human lung epithelial cells. Cr(VI)-transformed cells exhibited loss of contact inhibition, colony formation, and increased rates of cell invasion, migration, and proliferation, as compared with passage-matched control cells. Cr(VI)-transformed cells evaded apoptosis by a mechanism involving S-nitrosylation and stabilization of Bcl-2 protein in a nitric oxide-dependent manner. This study establishes an important in vitro model that facilitates mechanistic studies of Cr(VI)-induced carcinogenesis, and elucidates a novel mechanism that causes apoptosis-resistant malignant transformation of nontumorigenic lung cells in response to a human carcinogen.

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S-Nitrosylation of Bcl-2 Inhibits Its Ubiquitin-Proteasomal Degradation

Cited by 183 publications

References 59 publications

Nitric Oxide and Cancer Development

Nitric Oxide and Cancer Development

Nitric oxide: promoter or suppressor of programmed cell death?

Nitric Oxide–Mediated Bcl-2 Stabilization Potentiates Malignant Transformation of Human Lung Epithelial Cells

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