Cross-talk between calcium and reactive oxygen species signaling

Yuan, Yan; Wei, Chaoliang; Zhang, Wanrui; Cheng, Heping; Liu, Jie

doi:10.1111/j.1745-7254.2006.00390.x

Cited by 215 publications

(177 citation statements)

References 69 publications

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“…Calcium binding is the most represented function according to Gene Ontology terms and is affected by the expression of five out of the 32 genes shown in Figure 3 (fstl5, man1a1, efhd1, prkacb, and kcnip3). The regulation of calcium homeostasis is complex, but there is evidence that ROS and calcium signalling pathways interact (reviewed by Yan et al, 2006). The identification of the transcriptional regulation of several genes involved in calcium regulation suggests that there may be an even greater interplay between these two signalling molecules and bears further investigation.…”

Section: Discussionmentioning

confidence: 99%

Molecular consequences of SOD2 expression in epigenetically silenced pancreatic carcinoma cell lines

et al. 2007

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Manganese superoxide dismutase (SOD2) is an enzyme that catalyses the dismutation of superoxide in the mitochondria, leading to reduced levels of reactive oxygen species. Reduced expression levels of SOD2 have been shown to result in increased DNA damage and sod2 heterozygous mice have increased incidences of cancer. It has also been shown that SOD2 expression is lost in pancreatic cell lines, with reintroduction of SOD2 resulting in decreased rate of proliferation. The mechanism of decreased SOD2 expression in pancreatic carcinoma has not been previously determined. We demonstrate, through sodium bisulphite sequencing, that the sod2 locus is methylated in some pancreatic cell lines leading to a corresponding decrease in SOD2 expression. Methylation can be reversed by treatment with zebularine, a methyltransferase inhibitor, resulting in restored SOD2 expression. Furthermore, we demonstrate that sensitivity of pancreatic carcinoma cell lines to 2-methoxyestradiol correlates with SOD2 expression and SOD2 modulation can alter the sensitivity of these cells. Using both genomics and proteomics, we also identify molecular consequences of SOD2 expression in MIA-PaCa2 cells, including dephosphorylation of VEGFR2 and the identification of both SOD2-regulated genes and transcription factors with altered binding activity in response to SOD2 expression.

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Section: Discussionmentioning

confidence: 99%

Molecular consequences of SOD2 expression in epigenetically silenced pancreatic carcinoma cell lines

et al. 2007

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“…One such example was the calcium-binding protein calmodulin. An extensive and complex interaction between ROS and Ca 2+ has been identified (29). Under conditions of oxidative stress, calmodulin is selectively oxidized at critical methionine residues, allowing it to regulate the activity of several protein kinases and phosphatases (30).…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis Identifies Oxidative Stress Induction by Adaphostin

Stockwin

Bumke

et al. 2007

Clinical Cancer Research

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Purpose: Activities distinct from inhibition of Bcr/abl have led to adaphostin (NSC 680410) being described as “a drug in search of a mechanism.” In this study, proteomic analysis of adaphostin-treated myeloid leukemia cell lines was used to further elucidate a mechanism of action. Experimental Design: HL60 and K562 cells treated with adaphostin for 6, 12, or 24 h were analyzed using two-dimensional PAGE. Differentially expressed spots were excised, digested with trypsin, and analyzed by liquid chromatography–tandem mass spectrometry. The contribution of the redox-active hydroquinone group in adaphostin was also examined by carrying out proteomic analysis of HL60 cells treated with a simple hydroquinone (1,4-dihydroxybenzene) or H2O2. Results: Analysis of adaphostin-treated cells identified 49 differentially expressed proteins, the majority being implicated in the response to oxidative stress (e.g., CALM, ERP29, GSTP1, PDIA1) or induction of apoptosis (e.g., LAMA, FLNA, TPR, GDIS). Interestingly, modulation of these proteins was almost fully prevented by inclusion of an antioxidant, N-acetylcysteine. Validation of the proteomic data confirmed GSTP1 as an adaphostin resistance gene. Subsequent analysis of HL60 cells treated with 1,4-dihydroxybenzene or H2O2 showed similar increases in intracellular peroxides and an almost identical proteomic profiles to that of adaphostin treatment. Western blotting of a panel of cell lines identified Cu/Zn superoxide dismutase (SOD) as correlating with adaphostin resistance. The role of SOD as a second adaphostin resistance gene was confirmed by demonstrating that inhibition of SOD using diethyldithiocarbamate increased adaphostin sensitivity, whereas transfection of SOD I attenuated toxicity. Importantly, treatment with 1,4-dihydroxybenzene or H2O2 replicated adaphostin-induced Bcr/abl polypeptide degradation, suggesting that kinase inhibition is a ROS-dependent phenomenon. Conclusion: Adaphostin should be classified as a redox-active–substituted dihydroquinone.

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“…It also provides a stage for Ca 2+ and ROS to tango on. Ca 2+ modulates ROS homeostasis by regulating the ROS-generating and antioxidant systems, while ROS modify the components of the Ca 2+ signaling toolkit and reshape local and global Ca 2+ signal amplitudes and kinetics [1]. With the aid of a novel, reversible superoxide biosensor, mt-cpYFP, we recently discovered stochastic, discrete and transient superoxide production events, named superoxide flashes, in single mitochondria [2].…”

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confidence: 99%

Regulation of superoxide flashes by transient and steady mitochondrial calcium elevations

Jian

Hou

Yin

et al. 2014

Sci. China Life Sci.

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The mitochondria play essential roles in both intracellular calcium and reactive oxygen species signaling. As a newly discovered universal and fundamental mitochondrial phenomenon, superoxide flashes reflect transient bursts of superoxide production in the matrix of single mitochondria. Whether and how the superoxide flash activity is regulated by mitochondrial calcium remain largely unknown. Here we demonstrate that elevating mitochondrial calcium either by the calcium ionophore ionomycin or by increasing the bathing calcium in permeabilized HeLa cells increases superoxide flash incidence, and inhibition of the mitochondrial calcium uniporter activity abolishes the flash response. Quantitatively, the superoxide flash incidence is correlated to the steady-state mitochondrial calcium elevation with 1.7-fold increase per 1.0 F/F 0 of Rhod-2 signal. In contrast, large mitochondrial calcium transients (e.g., peak △F/F 0 ~2.8, duration ~2 min) in the absence of steady-state elevations failed to alter the flash activity. These results indicate that physiological levels of sustained, but not transient, mitochondrial calcium elevation acts as a potent regulator of superoxide flashes, but its mechanism of action likely involves a multi-step, slow-onset process. ) and reactive oxygen species (ROS) are important intracellular signaling molecules. The mitochondria play pivotal roles in both Ca 2+ handling and redox homeostasis. It also provides a stage for Ca 2+ and ROS to tango on. Ca 2+ modulates ROS homeostasis by regulating the ROS-generating and antioxidant systems, while ROS modify the components of the Ca 2+ signaling toolkit and reshape local and global Ca 2+ signal amplitudes and kinetics [1]. With the aid of a novel, reversible superoxide biosensor, mt-cpYFP, we recently discovered stochastic, discrete and transient superoxide production events, named superoxide flashes, in single mitochondria [2]. As a novel ROSgenerating activity, superoxide flash exists in isolated single mitochondria, cultured cells, ex vivo beating hearts and even living animals [2][3][4]. A superoxide flash event is initiated with transient opening of putative mitochondrial permeability transition pore (mPTP) and requires an intact mitochondrial electron transport chain (ETC) [2]. Functionally, superoxide flashes participate in the regulation of metabolism, cell proliferation and differentiation, hyperosmotic, inflammatory and oxidative stress responses, and even in the process of aging [5][6][7][8][9][10].Whether and how is superoxide flash activity intertwined with mitochondrial Ca 2+ signaling? Wang et al.[2] explored the relationship between Ca 2+ and superoxide flash in cardiac cells and found that superoxide flash frequency is unaltered by either a 2-fold increase or an abolition of Ca 2+ sparks. Hou et al. [5] found that elevating Ca 2+ or ROS

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Cross-talk between calcium and reactive oxygen species signaling

Cited by 215 publications

References 69 publications

Molecular consequences of SOD2 expression in epigenetically silenced pancreatic carcinoma cell lines

Molecular consequences of SOD2 expression in epigenetically silenced pancreatic carcinoma cell lines

Proteomic Analysis Identifies Oxidative Stress Induction by Adaphostin

Regulation of superoxide flashes by transient and steady mitochondrial calcium elevations

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