Human glutamate cysteine ligase gene regulation through the electrophile response element

Dickinson, David B.; Levonen, Anna–Liisa; Moellering, Douglas R.; Arnold, Erin K.; Zhang, Hongqiao; Darley‐Usmar, Victor

doi:10.1016/j.freeradbiomed.2004.06.011

Cited by 189 publications

(127 citation statements)

References 45 publications

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“…11 The EpRE is the cis-acting DNA element that mediates the NF-E2-related factor-2 (Nrf2)-dependent regulation of gene expression. 12 Downregulation of Nrf2 has been shown to reduce g-GCS gene expression and decrease GSH levels 13 and GSH-dependent enzymes. 14 Interestingly, Nrf2 levels have been directly associated with resistance to apoptosis.…”

Section: Figure 1 Apoptotic Signaling Pathways (See Text For Further mentioning

confidence: 99%

Apoptosis and glutathione: beyond an antioxidant

2009

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Apoptosis is a conserved homeostatic process critical for organ and tissue morphogenesis, development, and senescence. This form of programmed cell death also participates in the etiology of several human diseases including cancer, neurodegenerative, and autoimmune disorders. Although the signaling pathways leading to the progression of apoptosis have been extensively characterized, recent studies highlight the regulatory role of changes in the intracellular milieu (permissive apoptotic environment) in the efficient activation of the cell death machinery. In particular, glutathione (GSH) depletion is a common feature of apoptotic cell death triggered by a wide variety of stimuli including activation of death receptors, stress, environmental agents, and cytotoxic drugs. Although initial studies suggested that GSH depletion was only a byproduct of oxidative stress generated during cell death, recent discoveries suggest that GSH depletion and post-translational modifications of proteins through glutathionylation are critical regulators of apoptosis. Here, we reformulate these emerging paradigms into our current understanding of cell death mechanisms. Apoptosis or programmed cell death is a ubiquitous homeostatic process involved in numerous biological systems. Under physiological conditions it is critical not only in the turnover of cells in tissues but also during normal development and senescence. Moreover, its deregulation has been widely observed to occur as either a cause or consequence of distinct pathologies including cancer, autoimmune, and neurodegenerative diseases. Apoptosis is a highly organized program induced by a myriad of stimuli that are characterized by the progressive activation of precise pathways leading to specific biochemical and morphological alterations in individual cells without involving an inflammatory response. Early stages of apoptosis are characterized by initiator caspase activation, cell shrinkage, loss of plasma membrane lipid asymmetry, and chromatin condensation. The execution phase of apoptosis is characterized by activation of executioner caspases and endonucleases, apoptotic body formation, and cell fragmentation 1 (Figure 1). Interestingly, recent studies have shown that changes in the intracellular milieu of the cells, such as alterations in the redox environment, are important regulators of the progression to apoptosis. 2 These discoveries have lead to the concept of a permissive apoptotic environment necessary for the activation of the proper signaling pathways regulating apoptosis. Glutathione (GSH) depletion is an early hallmark in the progression of cell death in response to a variety of apoptotic stimuli in numerous cell types 3,4 (Figure 2), although the exact role of GSH depletion in apoptosis is still controversial. We review recent data that show new insights into the understanding of the causes and consequences that alterations in the redox environment of the cell have on apoptosis.The Role of GSH in the Regulation of Apoptosis GSH synthesis, depletion, and apopt...

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Section: Figure 1 Apoptotic Signaling Pathways (See Text For Further mentioning

confidence: 99%

Apoptosis and glutathione: beyond an antioxidant

2009

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“…Glutamate cysteine ligase (GCL) is the ratelimiting enzyme for GSH synthesis (12). GCL is a heterodimer composed by a catalytic or heavy subunit (GCLC) and a modulatory or light subunit (GCLM), which are encoded by different genes.…”

Section: The Gsh Content Increase Correlates With Gcl Expressionmentioning

confidence: 99%

Iron and glutathione at the crossroad of redox metabolism in neurons

et al. 2006

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Neurons, as non-dividing cells, encounter a myriad of stressful conditions throughout their lifespan. In particular, there is increasing evidence that iron progressively accumulates in the brain with age and that ironinduced oxidative stress is the cause of several forms of neurodegeneration. Here, we review recent evidence that gives support to the following notions: 1) neuronal iron accumulation leads to oxidative stress and cell death; 2) neuronal survival to iron accumulation associates with decreased expression of the iron import transporter DMT1 and increased expression of the efflux transporter IREG1; and 3) the adaptive process of neurons towards iron-induced oxidative stress includes a marked increase in both the expression of the catalytic subunit of gamma glutamate-cysteine ligase and glutathione. These findings may help to understand aging-related neurodegeneration hallmarks: oxidative damage, functional impairment and cell death.

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“…A major feature of Nrf2 stress response is to promote glutathione synthesis and recycling (2). The sharp increase in glutathione species (both reduced GSH and oxidized GSSG) was in accordance with the increase in both the catalytic and modifier subunits of the rate-limiting enzyme in the synthesis of GSH: ␥-glutamyl cysteine synthetase (42). After 14 days of exposure to chloroacetaldehyde, both transcript and protein levels of the glutamate-cysteine ligase catalytic and modifier subunits were increased (Table 3).…”

Section: Discussionmentioning

confidence: 53%

Nephron Toxicity Profiling via Untargeted Metabolome Analysis Employing a High Performance Liquid Chromatography-Mass Spectrometry-based Experimental and Computational Pipeline

Ranninger

Rurik

Limonciel

et al. 2015

Journal of Biological Chemistry

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Background: Drug toxicity testing calls for in vitro assays as alternatives to animal models. Results: OpenMS and KNIME are applicable for processing of HPLC-MS data sets to reveal metabolic changes upon chloroacetaldehyde treatment of kidney cells. Conclusion: Most significant changes are related to oxidative stress. Significance: Comprehensive multiomics studies support the risk assessment at an early stage of drug development.

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Human glutamate cysteine ligase gene regulation through the electrophile response element

Cited by 189 publications

References 45 publications

Apoptosis and glutathione: beyond an antioxidant

Apoptosis and glutathione: beyond an antioxidant

Iron and glutathione at the crossroad of redox metabolism in neurons

Nephron Toxicity Profiling via Untargeted Metabolome Analysis Employing a High Performance Liquid Chromatography-Mass Spectrometry-based Experimental and Computational Pipeline

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