Regulation of normal cell cycle progression by flavin-containing oxidases

Prakash, Venkatachalam; Toledo, Sonia M. de; Pandey, Badri N.; Tephly, Linda A.; Carter, A B; Little, John B.; Spitz, Douglas R.; Azzam, Edouard I.

doi:10.1038/sj.onc.1210634

Cited by 30 publications

(24 citation statements)

References 49 publications

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“…These results clearly showed that mammalian cells over expressing mutations in either SDHC or SDHD demonstrated low dose/low LET radio-sensitization. These results strongly support the hypothesis that metabolic sources of O 2 -, H 2 O 2 play a significant role in low dose radiation induced injury and suggest that scavengers of reactive oxygen species can be used to mitigate this injury process (3).…”

supporting

confidence: 82%

Mitochondrial-Derived Oxidants and Cellular Responses to Low Dose/Low LET Ionizing Radiation

Spitz¹

2009

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Oxidants and Cellular Responses to Low Dose/Low LET Ionizing Radiation"; Spitz, Douglas R. (Principal Investigator), 05/15/05 -12/31/09 A. Progress Report: The objective during the last period of support (5/15/05-12/31/09) was to determine the involvement of mitochondrial genetic defects in metabolic oxidative stress and the biological effects of low dose/low LET radiation. Aim 1 was to determine if cells with mutations in succinate dehydrogenase (SDH) subunits C and D (SDHC and SDHD in mitochondrial complex II) demonstrated increases in steady-state levels of reactive oxygen species (ROS; O 2 -and H 2 O 2 ) as well as demonstrating increased sensitivity to low dose/low LET radiation (10 cGy) in vitro. Aim #2 was to determine if specific mitochondrially-derived ROS contributed to increased sensitivity to low dose/low LET radiation in cells containing mutations in SDH subunits in vitro. Aim #3 was to determine if a causal relationship existed between persistent increases in mitochondrial ROS production, alterations in electron transport chain proteins, and genomic instability in the progeny of irradiated cells.Progress in Aim #1 and #2 included the isolation and characterization of SDHC and SDHD mutants in Chinese hamster fibroblasts that were found to demonstrate increased steady-state levels of O 2 -, H 2 O 2 as well as genomic instability (1, 2). The cells expressing SDHC mutations showed 3-fold increases steady-state levels of O 2 -

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supporting

confidence: 82%

Mitochondrial-Derived Oxidants and Cellular Responses to Low Dose/Low LET Ionizing Radiation

Spitz¹

2009

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“…Lucigenin Assay-The lucigenin assay was performed with cytosolic or mitochondrial protein (10 g) as previously described (19).…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial Cu,Zn-Superoxide Dismutase Mediates Pulmonary Fibrosis by Augmenting H2O2 Generation

He¹,

Murthy²,

McCormick³

et al. 2011

Journal of Biological Chemistry

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The release of H 2 O 2 from alveolar macrophages has been linked to the development of pulmonary fibrosis, but little is known about its source or mechanism of production. We found that alveolar macrophages from asbestosis patients spontaneously produce high levels of H 2 O 2 and have high expression of Cu,Zn-superoxide dismutase (SOD). Because Cu,Zn-SOD is found in the mitochondrial intermembrane space (IMS), we hypothesized that mitochondrial Cu,Zn-SOD-mediated H 2 O 2 generation contributed to pulmonary fibrosis. Asbestos-induced translocation of Cu,Zn-SOD to the IMS was unique to macrophages and dependent on functional mitochondrial respiration and the presence of at least one of the conserved cysteines required for disulfide bond formation. These conserved cysteine residues were also necessary for enzyme activation and

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“…JNK-mediated repression of MnSOD and catalase occur via mitochondrial complex I and NOX I (104). Among the main factors involved in the redox balancing in adaptive response to IR (119), ATM, NF-jB, and pre-inflammatory factors (134,135,224) may also be regulated via NOX (220). In addition, plasminogen activator inhibitor-1 is a redox-regulated factor involved in the induction of profibrogenic mediators in acute or chronic oxidative stress after exposure to IR or H 2 O 2 (244).…”

Section: Fig 3 Cyclin D1 Interacts Withmentioning

confidence: 99%

Cell Cycle Regulators Guide Mitochondrial Activity in Radiation-Induced Adaptive Response

Alexandrou

2014

Antioxidants & Redox Signaling

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Significance: There are accruing concerns on potential genotoxic agents present in the environment including low-dose ionizing radiation (LDIR) that naturally exists on earth's surface and atmosphere and is frequently used in medical diagnosis and nuclear industry. Although its long-term health risk is being evaluated and remains controversial, LDIR is shown to induce temporary but significant adaptive responses in mammalian cells and animals. The mechanisms guiding the mitochondrial function in LDIR-induced adaptive response represent a unique communication between DNA damage and cellular metabolism. Elucidation of the LDIRregulated mitochondrial activity may reveal new mechanisms adjusting cellular function to cope with hazardous environmental stress. Recent Advances: Key cell cycle regulators, including Cyclin D1/CDK4 and Cyclin B1/ cyclin-dependent kinase 1 (CDK1) complexes, are actively involved in the regulation of mitochondrial functions via phosphorylation of their mitochondrial targets. Accumulating new evidence supports a concept that the Cyclin B1/CDK1 complex acts as a mediator in the cross talk between radiation-induced DNA damage and mitochondrial functions to coordinate cellular responses to low-level genotoxic stresses. Critical Issues: The LDIR-mediated mitochondrial activity via Cyclin B1/CDK1 regulation is an irreplaceable network that is able to harmonize vital cellular functions with adjusted mitochondrial metabolism to enhance cellular homeostasis. Future Directions: Further investigation of the coordinative mechanism that regulates mitochondrial activities in sublethal stress conditions, including LDIR, will reveal new insights of how cells cope with genotoxic injury and will be vital for future targeted therapeutic interventions that reduce environmental injury and cancer risk.

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Regulation of normal cell cycle progression by flavin-containing oxidases

Cited by 30 publications

References 49 publications

Mitochondrial-Derived Oxidants and Cellular Responses to Low Dose/Low LET Ionizing Radiation

Mitochondrial-Derived Oxidants and Cellular Responses to Low Dose/Low LET Ionizing Radiation

Mitochondrial Cu,Zn-Superoxide Dismutase Mediates Pulmonary Fibrosis by Augmenting H2O2 Generation

Cell Cycle Regulators Guide Mitochondrial Activity in Radiation-Induced Adaptive Response

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