S-Nitrosylation of Ras Mediates Nitric Oxide-Dependent Post-Injury Neurogenesis in a Seizure Model

Santos, Ana Isabe; Carreira, Bruno P.; Izquierdo-Álvarez, Alicia; Ramos, Elena; Lourenço, Ana Sofia; Santos, Daniela F.; Morte, Maria Inês; Ribeiro, Luís F.; Marreiros, Ana; Sánchez-López, Nuria; Marina, Anabel; Carvalho, Caetana M.; Martínez‐Ruiz, Antonio; Araújo, Inês M.

doi:10.1089/ars.2016.6858

Cited by 13 publications

(16 citation statements)

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“…Although the Cys118 residue (present in the NKCD region, located in the invariant N -terminal domain up to amino acid 166) is considered the primary target of ROS and RNS [[12], [13], [14], [15], [16], [17]], the involvement of this residue in the redox-based modulation is controversial. Conflicting results likely reflect the use of different methodological approaches, redox inducers, and cell lines (Table 1).…”

Section: Cysteine-based Redox Regulation Of Ras Isoformsmentioning

confidence: 99%

“…Notably, the activation at the Golgi has been shown to facilitate the positive selection of T cells, whereas N-Ras activation at the plasma membrane has been reported to induce the negative selection of T cells [17]. Further, in mouse brain development, the iNOS-dependent S- nitrosylation of Cys118 of H-Ras has been shown to induce neurogenic effects on neuronal stem cells (NSC) [14]. Importantly, the mutation of Cys118 to Ser (Cys118Ser) renders the G-domain of H-Ras insensitive to ( i ) free radical activation, ( ii ) GTPase activity, ( iii ) the intrinsic and GEF-mediated guanine nucleotide dissociation rate, and ( iv ) the ability to bind effectors [[60], [61], [62], [63], [64], [65]].…”

Section: Cysteine-based Redox Regulation Of Ras Isoformsmentioning

confidence: 99%

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Cysteine-based regulation of redox-sensitive Ras small GTPases

Messina

Ascenzi

2019

Redox Biology

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Reactive oxygen and nitrogen species (ROS and RNS, respectively) activate the redox-sensitive Ras small GTPases. The three canonical genes ( HRAS, NRAS, and KRAS ) are archetypes of the superfamily of small GTPases and are the most common oncogenes in human cancer. Oncogenic Ras is intimately linked to redox biology, mainly in the context of tumorigenesis. The Ras protein structure is highly conserved, especially in effector-binding regions. Ras small GTPases are redox-sensitive proteins thanks to the presence of the NKCD motif (Asn116-Lys 117-Cys118-Asp119). Notably, the ROS- and RNS-based oxidation of Cys118 affects protein stability, activity, and localization, and protein-protein interactions. Cys residues at positions 80, 181, 184, and 186 may also help modulate these actions. Moreover, oncogenic mutations of Gly12Cys and Gly13Cys may introduce additional oxidative centres and represent actionable drug targets. Here, the pathophysiological involvement of Cys-redox regulation of Ras proteins is reviewed in the context of cancer and heart and brain diseases.

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Section: Cysteine-based Redox Regulation Of Ras Isoformsmentioning

confidence: 99%

Section: Cysteine-based Redox Regulation Of Ras Isoformsmentioning

confidence: 99%

Cysteine-based regulation of redox-sensitive Ras small GTPases

Messina

Ascenzi

2019

Redox Biology

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“…RAS glutathiolation in cysteine 118 has also been described as a posttranslational modification affecting RAS function that may provide a functional link between RAS proteins and cellular oxidative stress [ 104 ]. RAS proteins can also be nitrosylated, resulting in increased cell proliferation that is important for neurogenesis after seizure injury [ 105 , 106 ]. Finally, RAS can be also acetylated in lysine 104, a modification reported to negatively regulate RAS signaling by blocking RAS interaction with its GEFs, thus favoring the GDP-bound state [ 107 ].…”

Section: Further Advances On Ras Signaling During the 21st Centurymentioning

confidence: 99%

40 Years of RAS—A Historic Overview

Fernández‐Medarde

Rivas

Santos

2021

Genes

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It has been over forty years since the isolation of the first human oncogene (HRAS), a crucial milestone in cancer research made possible through the combined efforts of a few selected research groups at the beginning of the 1980s. Those initial discoveries led to a quantitative leap in our understanding of cancer biology and set up the onset of the field of molecular oncology. The following four decades of RAS research have produced a huge pool of new knowledge about the RAS family of small GTPases, including how they regulate signaling pathways controlling many cellular physiological processes, or how oncogenic mutations trigger pathological conditions, including developmental syndromes or many cancer types. However, despite the extensive body of available basic knowledge, specific effective treatments for RAS-driven cancers are still lacking. Hopefully, recent advances involving the discovery of novel pockets on the RAS surface as well as highly specific small-molecule inhibitors able to block its interaction with effectors and/or activators may lead to the development of new, effective treatments for cancer. This review intends to provide a quick, summarized historical overview of the main milestones in RAS research spanning from the initial discovery of the viral RAS oncogenes in rodent tumors to the latest attempts at targeting RAS oncogenes in various human cancers.

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“…In normal neurons, however, ERK1/2 plays essential roles in cell survival and should not be inhibited by S-nitrosylation [ 126 ]. Thus, S-nitrosylation instead takes place at the upstream protein p21 Ras , which conversely activates ERK1/2 pathway for neurogenesis [ 127 ]. Moreover, even in glioma cells, if S-nitrosylation is targeted to caspase-3, this inhibits its pro-apoptotic activity and promotes tumor cell growth [ 128 ].…”

Section: S-nitrosylation In Diseasesmentioning

confidence: 99%

S-Nitrosylation in Tumor Microenvironment

Sharma

Fernando

Letson

et al. 2021

IJMS

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S-nitrosylation is a selective and reversible post-translational modification of protein thiols by nitric oxide (NO), which is a bioactive signaling molecule, to exert a variety of effects. These effects include the modulation of protein conformation, activity, stability, and protein-protein interactions. S-nitrosylation plays a central role in propagating NO signals within a cell, tissue, and tissue microenvironment, as the nitrosyl moiety can rapidly be transferred from one protein to another upon contact. This modification has also been reported to confer either tumor-suppressing or tumor-promoting effects and is portrayed as a process involved in every stage of cancer progression. In particular, S-nitrosylation has recently been found as an essential regulator of the tumor microenvironment (TME), the environment around a tumor governing the disease pathogenesis. This review aims to outline the effects of S-nitrosylation on different resident cells in the TME and the diverse outcomes in a context-dependent manner. Furthermore, we will discuss the therapeutic potentials of modulating S-nitrosylation levels in tumors.

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S-Nitrosylation of Ras Mediates Nitric Oxide-Dependent Post-Injury Neurogenesis in a Seizure Model

Abstract: Our data highlight Ras SNO as an early event leading to NSC proliferation, and they may provide a target for NO-induced stimulation of neurogenesis with implications for brain repair. Antioxid. Redox Signal. 28, 15-30.

Cited by 13 publications

References 50 publications

Cysteine-based regulation of redox-sensitive Ras small GTPases

Cysteine-based regulation of redox-sensitive Ras small GTPases

40 Years of RAS—A Historic Overview

S-Nitrosylation in Tumor Microenvironment

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