Mechanism of Free Radical Nitric Oxide-mediated Ras Guanine Nucleotide Dissociation

Heo, Jongyun; Prutzman, Kirk C.; Mocanu, Viorel; Campbell, Sharon L.

doi:10.1016/j.jmb.2004.12.050

Cited by 64 publications

(115 citation statements)

References 79 publications

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“…The reversible regulation of proteins by nitrosothiols has been established as critical signaling mechanism by nNOS (40). Nanomolar NO has been reported to activate Ras posttranslationally, due to S-nitrosylation of critical Cys 118 residue, which stimulates guanine nucleotide exchange (44). Ras, a membranebound proto-oncogene, plays a key role as a molecular switch that links the activation of cell surface receptors with signaling cascades that control proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…MDA-MB-231 is one of the most malignant breast cancer cell lines, which contains numerous genetic mutations leading to overexpression of potential oncogenes. Growth factor receptor binding protein 2, which complexes with adaptor proteins involved in Ras signaling and HER-2, which increases the sensitivity of Ras signaling, are overexpressed in breast cancer cells (44)(45)(46)(47). In this biological setting, low concentration of NO could amplify Ras signaling by inducing conformational changes of the membrane-bound Ras protein.…”

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confidence: 99%

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Nitric Oxide in Physiologic Concentrations Targets the Translational Machinery to Increase the Proliferation of Human Breast Cancer Cells: Involvement of Mammalian Target of Rapamycin/eIF4E Pathway

et al. 2007

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Nitric oxide (NO) in nanomolar (nmol/L) concentrations is consistently detected in tumor microenvironment and has been found to promote tumorigenesis. The mechanism by which NO enhances tumor progression is largely unknown. In this study, we investigated the possible mechanisms and identified cellular targets by which NO increases proliferation of human breast cancer cell lines MDA-MB-231 and MCF-7. DETA-NONOate, a long acting NO donor, with a half-life of 20 h, was used. We found that NO (nmol/L) dramatically increased total protein synthesis in MDA-MB-231 and MCF-7 and also increased cell proliferation. NO specifically increased the translation of cyclin D1 and ornithine decarboxylase (ODC) without altering their mRNA levels or half-lives. Critical components in the translational machinery, such as phosphorylated mammalian target of rapamycin (mTOR) and its downstream targets, phosphorylated eukaryotic translation initiation factor and p70 S6 kinase, were up-regulated following NO treatment, and inhibition of mTOR with rapamycin attenuated NO induced increase of cyclin D1 and ODC. Activation of translational machinery was mediated by NO-induced up-regulation of the Raf/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase/ERK (Raf/MEK/ERK) and phosphatidylinositol 3-kinase (PI-3 kinase)/Akt signaling pathways. Up-regulation of the Raf/MEK/ ERK and PI-3 kinase/Akt pathways by NO was found to be mediated by activation of Ras, which was cyclic guanosine 3 ¶,5 ¶-monophosphate independent. Furthermore, inactivation of Ras by farnesyl transferase inhibitor or K-Ras small interfering RNA attenuated NO-induced increase in proliferation signaling and cyclin D1 and ODC translation, further confirming the involvement of Ras activation during NOinduced cell proliferation. [Cancer Res 2007;67(1):289-99]

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Nitric Oxide in Physiologic Concentrations Targets the Translational Machinery to Increase the Proliferation of Human Breast Cancer Cells: Involvement of Mammalian Target of Rapamycin/eIF4E Pathway

et al. 2007

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“…39,40 Given the >10-fold higher levels of cellular GTP compared with GDP, this enhanced exchange likely activates Ras. 41 In support of these findings, radical-mediated activation of Ras at Cys 118 contributes to tumor maintenance in a pancreatic cancer cell line and in a severe combined immunodeficiency/ beige mouse model.…”

Section: Nomentioning

confidence: 99%

Rho GTPases, oxidation, and cell redox control

et al. 2014

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“…Biologically relevant redox agents include nitric oxide (NO), nitrogen dioxide ( ⅐ NO 2 ), and dinitrogen trioxide (N 2 O 3 ) as well as the superoxide anion radical (O 2 . ) and hydrogen peroxide (25)(26)(27). Of these, ⅐ NO 2 and O 2 .…”

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confidence: 99%

Thiopurine Prodrugs Mediate Immunosuppressive Effects by Interfering with Rac1 Protein Function

Shin

Wey

Umutesi

et al. 2016

Journal of Biological Chemistry

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6-Thiopurine (6-TP) prodrugs include 6-thioguanine and azathioprine. Both are widely used to treat autoimmune disorders and certain cancers. This study showed that a 6-thioguanosine triphosphate (6-TGTP), converted in T-cells from 6-TP, targets Rac1 to form a disulfide adduct between 6-TGTP and the redox-sensitive GXXXXGK(S/T)C motif of Rac1. This study also showed that, despite the conservation of the catalytic activity of RhoGAP (Rho-specific GAP) on the 6-TGTP-Rac1 adduct to produce the biologically inactive 6-thioguanosine diphosphate (

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Mechanism of Free Radical Nitric Oxide-mediated Ras Guanine Nucleotide Dissociation

Cited by 64 publications

References 79 publications

Nitric Oxide in Physiologic Concentrations Targets the Translational Machinery to Increase the Proliferation of Human Breast Cancer Cells: Involvement of Mammalian Target of Rapamycin/eIF4E Pathway

Nitric Oxide in Physiologic Concentrations Targets the Translational Machinery to Increase the Proliferation of Human Breast Cancer Cells: Involvement of Mammalian Target of Rapamycin/eIF4E Pathway

Rho GTPases, oxidation, and cell redox control

Thiopurine Prodrugs Mediate Immunosuppressive Effects by Interfering with Rac1 Protein Function

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