Redox Regulation of Ras and Rho GTPases: Mechanism and Function

Mitchell, Lauren; Hobbs, G. Aaron; Aghajanian, Amir; Campbell, Sharon L.

doi:10.1089/ars.2012.4687

Cited by 84 publications

(76 citation statements)

References 58 publications

(88 reference statements)

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“…The malignant redox environment is closely interwoven with many oncogenes including RAS, to allow for tumor progression and metastasis (6,36,37). However, it is known that this crosstalk leads to an increase of cellular ROS production via overactivation of NADPH oxidases among others (38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

Hypoxic Signaling and the Cellular Redox Tumor Environment Determine Sensitivity to MTH1 Inhibition

et al. 2016

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Cancer cells are commonly in a state of redox imbalance that drives their growth and survival. To compensate for oxidative stress induced by the tumor redox environment, cancer cells upregulate specific nononcogenic addiction enzymes, such as MTH1 (NUDT1), which detoxifies oxidized nucleotides. Here, we show that increasing oxidative stress in nonmalignant cells induced their sensitization to the effects of MTH1 inhibition, whereas decreasing oxidative pressure in cancer cells protected against inhibition. Furthermore, we purified zebrafish MTH1 and solved the crystal structure of MTH1 bound to its inhibitor, highlighting the zebrafish as a relevant tool to study MTH1 biology. Delivery of 8-oxo-dGTP and 2-OH-dATP to zebrafish embryos was highly toxic in the absence of MTH1 activity.Moreover, chemically or genetically mimicking activated hypoxia signaling in zebrafish revealed that pathologic upregulation of the HIF1a response, often observed in cancer and linked to poor prognosis, sensitized embryos to MTH1 inhibition. Using a transgenic zebrafish line, in which the cellular redox status can be monitored in vivo, we detected an increase in oxidative pressure upon activation of hypoxic signaling. Pretreatment with the antioxidant N-acetyl-L-cysteine protected embryos with activated hypoxia signaling against MTH1 inhibition, suggesting that the aberrant redox environment likely causes sensitization. In summary, MTH1 inhibition may offer a general approach to treat cancers characterized by deregulated hypoxia signaling or redox imbalance. Cancer Res; 76(8); 2366-75. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Hypoxic Signaling and the Cellular Redox Tumor Environment Determine Sensitivity to MTH1 Inhibition

et al. 2016

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“…In fact, impaired cell migration after PDI silencing closely correlated with decreases in Rac1 or RhoA activity and profound disruption of cytoskeletal structures, such as stress fibers, focal adhesions, and adhesion vesicles. Importantly, Rac1 and RhoA can be strongly regulated by redox mechanisms, although it is yet unclear to what extent this occurs in vivo (118). Overall, these emerging findings allow the proposal that PDI may act as novel redox-related organizer of the NADPH oxidase complex.…”

Section: Pdi Interaction With Nox Nadph Oxidasementioning

confidence: 90%

Nox NADPH Oxidases and the Endoplasmic Reticulum

Laurindo

Araujo

Abrahão

2014

Antioxidants & Redox Signaling

161

138

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Significance: Understanding isoform-and context-specific subcellular Nox reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase compartmentalization allows relevant functional inferences. This review addresses the interplay between Nox NADPH oxidases and the endoplasmic reticulum (ER), an increasingly evident player in redox pathophysiology given its role in redox protein folding and stress responses. Recent Advances: Catalytic/regulatory transmembrane subunits are synthesized in the ER and their processing includes folding, N-glycosylation, heme insertion, p22phox heterodimerization, as shown for phagocyte Nox2. Dual oxidase (Duox) maturation also involves the regulation by ER-resident Duoxa2. The ER is the activation site for some isoforms, typically Nox4, but potentially other isoforms. Such location influences redox/Nox-mediated calcium signaling regulation via ER targets, such as sarcoendoplasmic reticulum calcium ATPase (SERCA). Growing evidence suggests that Noxes are integral signaling elements of the unfolded protein response during ER stress, with Nox4 playing a dual prosurvival/proapoptotic role in this setting, whereas Nox2 enhances proapoptotic signaling. ER chaperones such as protein disulfide isomerase (PDI) closely interact with Noxes. PDI supports growth factor-dependent Nox1 activation and mRNA expression, as well as migration in smooth muscle cells, and PDI overexpression induces acute spontaneous Nox activation. Critical Issues: Mechanisms of PDI effects include possible support of complex formation and RhoGTPase activation. In phagocytes, PDI supports phagocytosis, Nox activation, and redox-dependent interactions with p47phox. Together, the results implicate PDI as possible Nox organizer. Future Directions: We propose that convergence between Noxes and ER may have evolutive roots given ER-related functional contexts, which paved Nox evolution, namely calcium signaling and pathogen killing. Overall, the interplay between Noxes and the ER may provide relevant insights in Nox-related (patho)physiology. Antioxid. Redox Signal. 20, 2755Signal. 20, -2775

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“…Rho family GTPases containing this redox-sensitive motif include RhoA, RhoB, RhoC, RhoG, all Rac isoforms, and Cdc42 (for sequence comparison of the redox-sensitive motifs in Ras and Rho family GTPases, see ref. 6). The seminal papers that first identified the redox-sensitive properties of this motif in the canonical Rho family members (RhoA, Rac1, and Cdc42) showed that exposure to free radical oxidants (nitrogen dioxide and superoxide) resulted in increased nucleotide dissociation, similar to that observed for Ras.…”

Section: Redox Regulation Of Racmentioning

confidence: 99%