Rac1 Regulates Stress-induced, Redox-dependent Heat Shock Factor Activation

Ozaki, Michitaka; Deshpande, Shailesh; Angkeow, Piamsook; Suzuki, Seiichi; Irani, Kaikobad

doi:10.1074/jbc.m005287200

Cited by 82 publications

(60 citation statements)

References 45 publications

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“…A constitutively active Rac1 mutant does not increase intracellular ROS. Rac1 GTPase is, therefore, a necessary but not sufficient component of the pathway leading to ROS production during reoxygenation (87).…”

Section: Nadph Oxidasementioning

confidence: 99%

Reactive species mechanisms of cellular hypoxia-reoxygenation injury

Jackson

2002

American Journal of Physiology-Cell Physiology

938

673

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Li, Chuanyu, and Robert M. Jackson. Reactive species mechanisms of cellular hypoxia-reoxygenation injury. Am J Physiol Cell Physiol 282: C227-C241, 2002; 10.1152/ajpcell.00112.2001.-Exacerbation of hypoxic injury after restoration of oxygenation (reoxygenation) is an important mechanism of cellular injury in transplantation and in myocardial, hepatic, intestinal, cerebral, renal, and other ischemic syndromes. Cellular hypoxia and reoxygenation are two essential elements of ischemia-reperfusion injury. Activated neutrophils contribute to vascular reperfusion injury, yet posthypoxic cellular injury occurs in the absence of inflammatory cells through mechanisms involving reactive oxygen (ROS) or nitrogen species (RNS). Xanthine oxidase (XO) produces ROS in some reoxygenated cells, but other intracellular sources of ROS are abundant, and XO is not required for reoxygenation injury. Hypoxic or reoxygenated mitochondria may produce excess superoxide (O 2 Ϫ ) and release H2O2, a diffusible long-lived oxidant that can activate signaling pathways or react vicinally with proteins and lipid membranes. This review focuses on the specific roles of ROS and RNS in the cellular response to hypoxia and subsequent cytolytic injury during reoxygenation.anoxia; ischemia; reperfusion BACKGROUND

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Section: Nadph Oxidasementioning

confidence: 99%

Reactive species mechanisms of cellular hypoxia-reoxygenation injury

Jackson

2002

American Journal of Physiology-Cell Physiology

938

673

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“…The insight gained from characterization of the neutrophil NADPH oxidase system prompted several laboratories to address whether analogous systems existed in nonphagocytic cells. Evidence that a nonphagocytic NADPH oxidase existed was bolstered by the observation that expression of constitutively activated forms of Rac1 was capable of increasing intracellular ROS levels in a variety of nonphagocytic cells (10)(11)(12)(13)(14)(15). In addition, a dominant negative form of Rac1 was shown to be able to block ROS production from a number of different cytokines or growth factors (10).…”

mentioning

confidence: 99%

Reactive Oxygen Species and Signal Transduction

Finkel¹

2001

IUBMB Life

261

199

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SummaryIncreasing evidence suggests a role for intracellular reactive oxygen species (ROS) as mediators of normal and pathological signal transduction pathways. In particular, a growing list of recent reports have demonstrated a rapid and signi cant increases in intracellular ROS following growth factor or cytokine stimulation. These ROS appear essential for a host of downstream signaling events. Biochemical characterization of this ligand-activated ROS production has revealed important information regarding the molecular composition of the cellular oxidases and the regulation of their activity by small GTPases. Work is proceeding on identifying strategies to identify how ROS might speci cally regulate signaling pathways by altering the activity of direct target molecules. This review will focus on the progress in the rapid emerging area of oxidant or redox-dependent signal transduction and speculate how these insights might alter our view and treatment of diseases thought to be caused by oxidative stress. It has been well known that bacteria respond to changes in the concentration of either superoxide anion or hydrogen peroxide with a precise signaling pathway and a corresponding discrete set of induced gene expression (1). The pattern of gene expression differs depending on whether the bacteria is exposed to either superoxide anions or hydrogen peroxide. This speci city suggests that the response to ROS is not a generalized stress response but instead has evolved to allow bacteria to be able to sense, and respond accordingly, to subtly different oxidant species. Although the ability of bacteria to sense and respond to changes in intracellular ROS has been appreciated for some time, the realization that eukaryotic cells might have similar abilities has only recently been advanced. Over the last 5 years, a growing number of reports have suggested that mammalian cells can rapidly respond to ligand stimulation with a change in intracellular ROS. For many of these reports, investigators have used uorescent dyes to measure the level of intracellular ROS in living cells. These dyes, dichloro uorescein diacetate (DCFDA) being the most common, are readily available and their ease of use has spurred interest in the eld. Many of these compounds are non uorescent moieties that, when oxidized by ROS form uorescent compounds, can be imaged by standard uorescent or confocal microscopy. Although the use of compounds such as DCFDA is widespread, it is important to note that the speci city of these compounds for their intended ROS species (in the case of DCFDA, hydrogen peroxide) is not well established. In addition, at present it is impossible to determine absolute levels of ROS from the uorescent intensity and, as such, these measurements represent a qualitative, (not quantitative) assessment of ligand-activated ROS production.With these caveats in mind, the last few years have seen a growing number of reports demonstrating that ROS production represents a common aspect of multiple signaling pathways. Included among these lig...

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“…Rac proteins, in particular rac1, function similarly in nonphagocytic cells, 1,12 and such rac1-regulated ROS have been implicated in a variety of cellular processes including growth, migration, and transformation. 2,8,[12][13][14][15][16][17] We have recently shown that rac1-regulated ROS production also mediates apoptosis in response to I/R. 7 Hepatocyte growth factor (HGF), which was initially isolated as a potent mitogen for hepatocytes, is now known to be a broad-spectrum mitogen for a variety of cell types.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3][4][5] There are accumulating data indicating that regulation of the intracellular redox state is a versatile control mechanism in signal transduction in both pathological and physiological conditions. 6 Ischemia/reperfusion (I/R) and hypoxia/reoxygenation (H/ R) result in the production of ROS within tissue or cells.…”

Section: Introductionmentioning

confidence: 99%

“…6 Ischemia/reperfusion (I/R) and hypoxia/reoxygenation (H/ R) result in the production of ROS within tissue or cells. 2,7,8 The rac1 small GTPase is an important regulator of ROS production within cells under these circumstances. 7 Rac1 belongs to the rho family of small GTP binding proteins and its role in the production of ROS in phagocytic cells such as neutrophils is well established.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of hypoxia/reoxygenation-induced oxidative stress in HGF-stimulated antiapoptotic signaling: role of PI3-K and Akt kinase upon rac1

et al. 2003

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Rac1-regulated reactive oxygen species (ROS) production has been implicated in apoptosis. In contrast, pleiotropic protein kinase Akt protects against apoptosis. However, the pro-and antiapoptotic mechanisms of rac1 and Akt, respectively, and the intersection between these mechanisms are incompletely understood. In a model of oxidative stress and apoptosis induced by hypoxia/reoxygenation (H/R) in primary hepatocytes, activation of the PI3-K Akt axis by the prosurvival hepatocyte growth factor (HGF) inhibited H/Rstimulated rac1 activation and intracellular ROS production, and suppressed apoptosis. Suppression of PI3-K or Akt activity abrogated the inhibitory effect of HGF on rac1 activity and rac1-regulated oxidative stress. Furthermore, constitutive activation of Akt or PI3-K in the absence of HGF was sufficient to phosphorylate rac1, inhibit rac1 activation, and suppress rac1-regulated ROS production. These findings demonstrate that growth factor-stimulated activation of PI3-K-Akt is necessary and sufficient to suppress intracellular oxidative stress and apoptosis by inhibiting activation of proapoptotic, prooxidative rac1 GTPase.

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Rac1 Regulates Stress-induced, Redox-dependent Heat Shock Factor Activation

Cited by 82 publications

References 45 publications

Reactive species mechanisms of cellular hypoxia-reoxygenation injury

Reactive species mechanisms of cellular hypoxia-reoxygenation injury

Reactive Oxygen Species and Signal Transduction

Inhibition of hypoxia/reoxygenation-induced oxidative stress in HGF-stimulated antiapoptotic signaling: role of PI3-K and Akt kinase upon rac1

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