Search tips
Search criteria

Results 1-25 (556)

Clipboard (0)

Select a Filter Below

Year of Publication
1.  Can Telomere Shortening in Human Peripheral Blood Leukocytes Serve as a Disease Biomarker of Friedreich's Ataxia? 
Antioxidants & Redox Signaling  2013;18(11):1303-1306.
Enhanced oxidative stress and inflammation contribute to telomere erosion. Friedreich's ataxia is a neurodegenerative disorder caused by a reduction in frataxin expression that results in mitochondrial dysfunction and oxidative damage. Furthermore, frataxin deficiency induces a strong activation of inflammatory genes and neuronal death. We investigated telomere length (TL) in peripheral blood leukocytes of 37 patients with Friedreich's ataxia and 36 controls. We noted a significant telomere shortening in patients with Friedreich's ataxia compared to healthy controls (p=0.03). We also found a correlation between TL and disease duration (p=0.001). Our observations lead to the hypothesis that the TL of human peripheral blood leukocytes may serve as a biomarker of Friedreich's ataxia that could be used as an outcome measure in clinical trials. Antioxid. Redox Signal. 18, 1303–1306.
PMCID: PMC3584504  PMID: 23146029
2.  Aldose Reductase Inhibition Prevents Colon Cancer Growth by Restoring Phosphatase and Tensin Homolog Through Modulation of miR-21 and FOXO3a 
Antioxidants & Redox Signaling  2013;18(11):1249-1262.
Aims: We have shown earlier that inhibition of aldose reductase (AR), an oxidative stress-response protein, prevents colon cancer cell growth in vitro and in vivo. Changes in microribonucleic acid (miR) expression can contribute to cancer by modulating the functional expression of critical genes involved in cancer growth and metastasis. However, the molecular mechanisms by which AR regulates miR expression and their dependent mitogenic effects in cancer cells are not known. Therefore, we investigated how AR regulates growth factor-induced expression of miRs and growth of colon cancer cells. Results: Inhibition of AR significantly downregulated growth factor-induced miR-21 expression in human colon cancer cells, HT29, SW480, and Caco-2. Further, AR inhibition also increased phosphatase and tensin homolog (PTEN) (a direct target of miR-21) and forkhead box O3A (FOXO3a) in colon cancer cells. Our results obtained with HT29 cells ablated with FOXO3a siRNA showed increased activator protein-1 (AP-1) activation and miR-21 expression, indicating that FOXO3a represses miR-21 via AP-1 inactivation. Inhibition of AR also prevented the epidermal growth factor-induced phosphorylation of phosphatidylinositol 3-kinase (PI3K), serine/threonine kinase (AKT), c-Jun, c-Fos, PTEN, and FOXO3a, and deoxyribonucleic acid (DNA)-binding activity of AP-1. More importantly, in human colon adenocarcinoma xenograft tissues, miR-21 expression was lower, and PTEN and FOXO3a levels were significantly higher in AR inhibitor-treated mice compared to controls. Innovation: These findings demonstrate a novel role of AR in the regulation of miR-21 and its target PTEN in growth factor-induced colon cancer cell growth. Conclusions: Collectively, these results show a novel role of AR in mediation of growth factor-induced colon cancer growth by modulating miR-21, PTEN, and FOXO3a expression through reactive oxygen species (ROS)/PI3K/AKT/AP-1. Antioxid. Redox Signal. 18, 1249–1262.
PMCID: PMC3584509  PMID: 22978663
3.  S-Bacillithiolation Protects Conserved and Essential Proteins Against Hypochlorite Stress in Firmicutes Bacteria 
Antioxidants & Redox Signaling  2013;18(11):1273-1295.
Aims: Protein S-bacillithiolations are mixed disulfides between protein thiols and the bacillithiol (BSH) redox buffer that occur in response to NaOCl in Bacillus subtilis. We used BSH-specific immunoblots, shotgun liquid chromatography (LC)–tandem mass spectrometry (MS/MS) analysis and redox proteomics to characterize the S-bacillithiolomes of B. subtilis, B. megaterium, B. pumilus, B. amyloliquefaciens, and Staphylococcus carnosus and also measured the BSH/oxidized bacillithiol disulfide (BSSB) redox ratio after NaOCl stress. Results: In total, 54 proteins with characteristic S-bacillithiolation (SSB) sites were identified, including 29 unique proteins and eight proteins conserved in two or more of these bacteria. The methionine synthase MetE is the most abundant S-bacillithiolated protein in Bacillus species after NaOCl exposure. Further, S-bacillithiolated proteins include the translation elongation factor EF-Tu and aminoacyl-tRNA synthetases (ThrS), the DnaK and GrpE chaperones, the two-Cys peroxiredoxin YkuU, the ferredoxin–NADP+ oxidoreductase YumC, the inorganic pyrophosphatase PpaC, the inosine-5′-monophosphate dehydrogenase GuaB, proteins involved in thiamine biosynthesis (ThiG and ThiM), queuosine biosynthesis (QueF), biosynthesis of aromatic amino acids (AroA and AroE), serine (SerA), branched-chain amino acids (YwaA), and homocysteine (LuxS and MetI). The thioredoxin-like proteins, YphP and YtxJ, are S-bacillithiolated at their active sites, suggesting a function in the de-bacillithiolation process. S-bacillithiolation is accompanied by a two-fold increase in the BSSB level and a decrease in the BSH/BSSB redox ratio in B. subtilis. Innovation: Many essential and conserved proteins, including the dominant MetE, were identified in the S-bacillithiolome of different Bacillus species and S. carnosus using shotgun-LC-MS/MS analyses. Conclusion: S-bacillithiolation is a widespread redox control mechanism among Firmicutes bacteria that protects conserved metabolic enzymes and essential proteins against overoxidation. Antioxid. Redox Signal. 18, 1273–1295.
PMCID: PMC3584511  PMID: 22938038
4.  The Protective Role of the Transmembrane Thioredoxin-Related Protein TMX in Inflammatory Liver Injury 
Antioxidants & Redox Signaling  2013;18(11):1263-1272.
Aims: Accumulating evidence indicates that oxidative stress is associated with inflammation, and the cellular redox status can determine the sensitivity and the final outcome in response to inflammatory stimuli. To control the redox balance, mammalian cells contain a variety of oxidoreductases belonging to the thioredoxin superfamily. The large number of these enzymes suggests a complex mechanism of redox regulation in mammals, but the precise function of each family member awaits further investigations. Results: We generated mice deficient in transmembrane thioredoxin-related protein (TMX), a transmembrane oxidoreductase in the endoplasmic reticulum (ER). When exposed to lipopolysaccharide (LPS) and d-(+)-galactosamine (GalN) to induce inflammatory liver injury, mutant mice were highly susceptible to the toxicants and developed severe liver damage. LPS-induced production of inflammatory mediators was equivalent in both wild-type and TMX−/− mice, whereas neutralization of the proinflammatory cytokine tumor necrosis factor-α suppressed the toxic effects of LPS/GalN in the mutant mice. Liver transcriptional profiles revealed enhanced activation of the p53-signaling pathway in the TMX−/− mice after LPS/GalN treatment. Furthermore, TMX deficiency also caused increased sensitivity to thioacetamide, which exerts its hepatotoxicity through the generation of reactive oxygen species. Innovation: The present study is the first to address the role of the oxidoreductase TMX in inflammatory liver injury. The phenotype of mice deficient in TMX suggests a functional link between redox regulation in the ER and susceptibility to oxidative tissue damage. Conclusion: We conclude that TMX plays a major role in host defense under the type of inflammatory conditions associated with oxidative stress. Antioxid. Redox Signal. 18, 1263–1272.
PMCID: PMC3584524  PMID: 22924822
5.  Redox Control of Leukemia: From Molecular Mechanisms to Therapeutic Opportunities 
Antioxidants & Redox Signaling  2013;18(11):1349-1383.
Reactive oxygen species (ROS) play both positive and negative roles in the proliferation and survival of a cell. This dual nature has been exploited by leukemia cells to promote growth, survival, and genomic instability—some of the hallmarks of the cancer phenotype. In addition to altered ROS levels, many antioxidants are dysregulated in leukemia cells. Together, the production of ROS and the expression and activity of antioxidant enzymes make up the primary redox control of leukemia cells. By manipulating this system, leukemia cells gain proliferative and survival advantages, even in the face of therapeutic insults. Standard treatment options have improved leukemia patient survival rates in recent years, although relapse and the development of resistance are persistent challenges. Therapies targeting the redox environment show promise for these cases. This review highlights the molecular mechanisms that control the redox milieu of leukemia cells. In particular, ROS production by the mitochondrial electron transport chain, NADPH oxidase, xanthine oxidoreductase, and cytochrome P450 will be addressed. Expression and activation of antioxidant enzymes such as superoxide dismutase, catalase, heme oxygenase, glutathione, thioredoxin, and peroxiredoxin are perturbed in leukemia cells, and the functional consequences of these molecular alterations will be described. Lastly, we delve into how these pathways can be potentially exploited therapeutically to improve treatment regimens and promote better outcomes for leukemia patients. Antioxid. Redox Signal. 18, 1349–1383.
I. Introduction
II. How Does ROS Affect Leukemia?
A. Background on leukemia
B. Leukemic oncogenes
C. How do leukemic oncogenes control the redox environment?
III. Mechanisms of ROS Production in Leukemia
A. Mitochondrial respiration: a source of life and death for the leukemia cell
B. NOX as a source of oncogene-induced ROS
C. Metabolic/detoxification pathways and ROS production in leukemia
IV. Cellular Antioxidants in Leukemia
A. Nrf2: a master regulator of antioxidant transcription
B. Enzymatic elimination of ROS
1. Superoxide dismutase
2. Catalase
3. Heme oxygenase
4. Glutathione
5. Thioredoxin
6. Peroxiredoxin
V. ROS-Dependent Therapeutic Agents
A. Standard-of-care chemotherapeutic agents and modulation of oxidative stress
1. Purine analogs: cytarabine and fludarabine
2. Mitotic inhibitor: vincristine
3. Anthracyclines
B. Recently approved ROS-producing agents
1. Arsenic trioxide
2. Histone deacetylase inhibitors
3. Proteasome inhibitors
C. Preclinical redox modifying compounds for the treatment of leukemia
1. Preclinical ROS inhibition
a. NOX inhibitors
b. Xanthine oxidoreductase inhibitors
c. SOD and catalase delivery
2. Preclinical ROS induction
a. HO-1 inhibitors (protoporphyrins)
b. Trx pathway inhibitors
c. Isothiocyanates
d. Adaphostin
e. Piperlongumine
f. Parthenolide
VI. Summary/Remarks
PMCID: PMC3584825  PMID: 22900756
6.  Coupling Heme and Iron Metabolism via Ferritin H Chain 
Antioxidants & Redox Signaling  2014;20(11):1754-1769.
Significance: Inflammation and immunity can be associated with varying degrees of heme release from hemoproteins, eventually leading to cellular and tissue iron (Fe) overload, oxidative stress, and tissue damage. Presumably, these deleterious effects contribute to the pathogenesis of systemic infections. Recent Advances: Heme release from hemoglobin sensitizes parenchyma cells to undergo programmed cell death in response to proinflammatory cytokines, such as tumor necrosis factor. This cytotoxic effect is driven by a mechanism involving intracellular accumulation of free radicals, which sustain the activation of the c-Jun N-terminal kinase (JNK) signaling transduction pathway. While heme catabolism by heme oxygenase-1 (HO-1) prevents programmed cell death, this cytoprotective effect requires the co-expression of ferritin H (heart/heavy) chain (FTH), which controls the pro-oxidant effect of labile Fe released from the protoporphyrin IX ring of heme. This antioxidant effect of FTH restrains JNK activation, whereas JNK activation inhibits FTH expression, a cross talk that controls metabolic adaptation to cellular Fe overload associated with systemic infections. Critical Issues and Future Directions: Identification and characterization of the mechanisms via which FTH provides metabolic adaptation to tissue Fe overload should provide valuable information to our current understanding of the pathogenesis of systemic infections as well as other immune-mediated inflammatory diseases. Antioxid. Redox Signal. 20, 1754–1769.
PMCID: PMC3961798  PMID: 24124891
7.  Heme Oxygenase-1 Is Required for Angiogenic Function of Bone Marrow-Derived Progenitor Cells: Role in Therapeutic Revascularization 
Antioxidants & Redox Signaling  2014;20(11):1677-1692.
Aims: Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that can be down-regulated in diabetes. Its importance for mature endothelium has been described, but its role in proangiogenic progenitors is not well known. We investigated the effect of HO-1 on the angiogenic potential of bone marrow-derived cells (BMDCs) and on blood flow recovery in ischemic muscle of diabetic mice. Results: Lack of HO-1 decreased the number of endothelial progenitor cells (Lin−CD45−cKit-Sca-1+VEGFR-2+) in murine bone marrow, and inhibited the angiogenic potential of cultured BMDCs, affecting their survival under oxidative stress, proliferation, migration, formation of capillaries, and paracrine proangiogenic potential. Transcriptome analysis of HO-1−/− BMDCs revealed the attenuated up-regulation of proangiogenic genes in response to hypoxia. Heterozygous HO-1+/− diabetic mice subjected to hind limb ischemia exhibited reduced local expression of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), stromal cell-derived factor 1 (SDF-1), VEGFR-1, VEGFR-2, and CXCR-4. This was accompanied by impaired revascularization of ischemic muscle, despite a strong mobilization of bone marrow-derived proangiogenic progenitors (Sca-1+CXCR-4+) into peripheral blood. Blood flow recovery could be rescued by local injections of conditioned media harvested from BMDCs, but not by an injection of cultured BMDCs. Innovation: This is the first report showing that HO-1 haploinsufficiency impairs tissue revascularization in diabetes and that proangiogenic in situ response, not progenitor cell mobilization, is important for blood flow recovery. Conclusions: HO-1 is necessary for a proper proangiogenic function of BMDCs. A low level of HO-1 in hyperglycemic mice decreases restoration of perfusion in ischemic muscle, which can be rescued by a local injection of conditioned media from cultured BMDCs. Antioxid. Redox Signal. 20, 1677–1692.
PMCID: PMC3961799  PMID: 24206054
8.  In African American Type 2 Diabetic Patients, Is Vitamin D Deficiency Associated with Lower Blood Levels of Hydrogen Sulfide and Cyclic Adenosine Monophosphate, and Elevated Oxidative Stress? 
Antioxidants & Redox Signaling  2013;18(10):1154-1158.
African Americans (AA) have a higher incidence of cardiovascular disease and vitamin D (VD) deficiency compared with Caucasians. Hydrogen sulfide (H2S) is an important signaling molecule. This study examined the hypothesis that blood levels of H2S are lower in AA type 2 diabetic patients (T2D). Fasting blood was obtained from T2D and healthy controls. Results showed a significant decrease in plasma levels of cyclic adenosine monophosphate (cAMP) and H2S in AA T2D but not in Caucasian T2D when compared with those of respective age- and race-matched healthy controls. Plasma VD levels were significantly lower in AA T2D compared with Caucasian T2D. Cell culture studies demonstrate that 1,25(OH)2-VD supplementation significantly increased expression of cystathionine-γ-lyase (CSE), H2S formation, and cAMP secretion, but decreased reactive oxygen species in high glucose-treated U937 monocytes. This suggests that VD supplementation upregulates CSE and H2S formation and decreases oxidative stress, and that VD deficiency may contribute to the malfunctioning of H2S signaling and thus a higher incidence of vascular inflammation in AA. These results lead to the hypothesis that VD supplementation can replenish blood concentrations of H2S and cAMP and lower oxidative stress and cardiovascular disease in AA T2D. Antioxid. Redox Signal. 18, 1154–1158.
PMCID: PMC3579382  PMID: 22852873
9.  Thioredoxin and Thioredoxin Target Proteins: From Molecular Mechanisms to Functional Significance 
Antioxidants & Redox Signaling  2013;18(10):1165-1207.
The thioredoxin (Trx) system is one of the central antioxidant systems in mammalian cells, maintaining a reducing environment by catalyzing electron flux from nicotinamide adenine dinucleotide phosphate through Trx reductase to Trx, which reduces its target proteins using highly conserved thiol groups. While the importance of protecting cells from the detrimental effects of reactive oxygen species is clear, decades of research in this field revealed that there is a network of redox-sensitive proteins forming redox-dependent signaling pathways that are crucial for fundamental cellular processes, including metabolism, proliferation, differentiation, migration, and apoptosis. Trx participates in signaling pathways interacting with different proteins to control their dynamic regulation of structure and function. In this review, we focus on Trx target proteins that are involved in redox-dependent signaling pathways. Specifically, Trx-dependent reductive enzymes that participate in classical redox reactions and redox-sensitive signaling molecules are discussed in greater detail. The latter are extensively discussed, as ongoing research unveils more and more details about the complex signaling networks of Trx-sensitive signaling molecules such as apoptosis signal-regulating kinase 1, Trx interacting protein, and phosphatase and tensin homolog, thus highlighting the potential direct and indirect impact of their redox-dependent interaction with Trx. Overall, the findings that are described here illustrate the importance and complexity of Trx-dependent, redox-sensitive signaling in the cell. Our increasing understanding of the components and mechanisms of these signaling pathways could lead to the identification of new potential targets for the treatment of diseases, including cancer and diabetes. Antioxid. Redox Signal. 18, 1165–1207.
I. Introduction
A. Redox control and signaling in the cell
B. Thioredoxin
C. Trx reductase
1. Background
2. Regulation
3. Clinical significance
D. Trx target proteins
II. Reductive Enzymes
A. Peroxiredoxins
1. Background
2. Regulation
3. Clinical significance
B. Ribonucleotide reductase
1. Background
2. Regulation
3. Clinical significance
C. Methionine sulfoxide reductase
1. Background
2. Regulation
3. Clinical significance
III. Trx-Sensitive Signaling Molecules
A. Apoptosis signal-regulating kinase-1
1. Background
a. Mitogen-activated protein kinase signaling cascades
(1) ERK signaling pathway
(2) JNK and p38 signaling pathways
b. Structure and function
c. ASK1 signalosome
2. Regulation
a. Post-translational regulation
(1) Phosphorylation
(2) Ubiquitination
(3) S-nitrosylation
b. Protein-protein interactions
(1) Thioredoxin
(2) Trx interacting protein
(3) Glutaredoxin
(4) Ser/Thr protein phosphatase 5
3. ASK1 in health and diseases
a. Innate immune response signaling
b. Cardiac hypertrophy and remodeling
c. Neurodegenerative diseases and ER stress
d. Cancer
e. Diabetes
4. Conclusion
B. Trx interacting protein
1. Background
2. Regulation
a. Transcriptional regulation
b. Post-transcriptional regulation
c. Post-translational regulation
3. Txnip in health and disease
a. Development, differentiation, and proliferation
b. Metabolism
c. Cardiovascular system
d. Other organ systems
(1) Kidney
(2) Eye
(3) Peripheral nervous system
(4) Liver
4. Conclusion
C. Phosphatase and tensin homolog
1. Background
a. Phosphatidylinositol 3-kinase signaling pathway
b. Structure and function
2. Regulation
a. Transcriptional regulation
b. Post-transcriptional regulation
c. Post-translational regulation
(1) Phosphorylation and protein oxidation
(2) Ubiquitination
(3) Acetylation
d. Localization
e. Protein-protein interactions
3. PTEN in health and disease
a. PTEN hamartoma tumor syndrome
b. Embryonic development
c. Cancer
(1) Lung cancer
(2) Hepatocellular carcinoma
(3) Prostate cancer
(4) Breast cancer
d. Diabetes
4. Conclusion
PMCID: PMC3579385  PMID: 22607099
10.  Oxygen Consumption and Usage During Physical Exercise: The Balance Between Oxidative Stress and ROS-Dependent Adaptive Signaling 
Antioxidants & Redox Signaling  2013;18(10):1208-1246.
The complexity of human DNA has been affected by aerobic metabolism, including endurance exercise and oxygen toxicity. Aerobic endurance exercise could play an important role in the evolution of Homo sapiens, and oxygen was not important just for survival, but it was crucial to redox-mediated adaptation. The metabolic challenge during physical exercise results in an elevated generation of reactive oxygen species (ROS) that are important modulators of muscle contraction, antioxidant protection, and oxidative damage repair, which at moderate levels generate physiological responses. Several factors of mitochondrial biogenesis, such as peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), mitogen-activated protein kinase, and SIRT1, are modulated by exercise-associated changes in the redox milieu. PGC-1α activation could result in decreased oxidative challenge, either by upregulation of antioxidant enzymes and/or by an increased number of mitochondria that allows lower levels of respiratory activity for the same degree of ATP generation. Endogenous thiol antioxidants glutathione and thioredoxin are modulated with high oxygen consumption and ROS generation during physical exercise, controlling cellular function through redox-sensitive signaling and protein–protein interactions. Endurance exercise-related angiogenesis, up to a significant degree, is regulated by ROS-mediated activation of hypoxia-inducible factor 1α. Moreover, the exercise-associated ROS production could be important to DNA methylation and post-translation modifications of histone residues, which create heritable adaptive conditions based on epigenetic features of chromosomes. Accumulating data indicate that exercise with moderate intensity has systemic and complex health-promoting effects, which undoubtedly involve regulation of redox homeostasis and signaling. Antioxid. Redox Signal. 18, 1208–1246.
I. Introduction
II. General Adaptations to Exercise
III. Exercise, ROS, Antioxidant, and Housekeeping Systems
A. ROS and antioxidants
B. Thiols and redox signaling in exercise
C. Oxidative damage and housekeeping
IV. ROS, Metabolism, and Exercise
A. Sirtuins as redox-sensitive energy sensors of exercise
B. Redox signaling and biogenesis of mitochondria
V. Exercise-Induced Inflammation and ROS
VI. The Crucial Role of Redox Regulation on New Cell Formation in Skeletal Muscle and Brain
VII. Exercise, ROS and Oxygen Sensing, HIF, and Vascular Endothelial Growth Factor
A. Hypoxia in skeletal muscle
B. HIF-1α-independent regulation of VEGF and angiogenesis
C. p38γ MAPK/PGC-1α signaling regulation by physical exercise and its significance for mitochondrial biogenesis and angiogenesis in skeletal muscle
D. Two-faced ROS in HIF activation
E. Effect of exercise on HIF and VEGF signaling
VIII. Exercise, ROS, and Epigenetics
IX. Conclusion
PMCID: PMC3579386  PMID: 22978553
11.  Nitrosative Stress Plays an Important Role in Wnt Pathway Activation in Diabetic Retinopathy 
Antioxidants & Redox Signaling  2013;18(10):1141-1153.
Aims: Diabetes is associated with nitrosative stress in multiple tissues. Overactivation of the Wnt pathway has been shown to play a pathogenic role in diabetic retinopathy (DR). The purpose of this study was to investigate whether nitrosative stress contributes to aberrant activation of Wnt signaling in diabetes. Results: Nitrosative stress induced by peroxynitrite (PN), 4-hydroxynonenal (HNE), or high glucose (HG) in retinal cells was assessed by a dichlorofluorescein fluorescence assay or by Western blot analysis and enzyme-linked immunosorbent assay of 3-nitrotyrosine (3-NT). These nitrosative stress inducers activated the canonical Wnt pathway, as shown by Western blot analysis of phosphorylated low-density lipoprotein receptor-related protein 6 (pLRP6), total and nuclear β-catenin levels, Luciferase reporter assay, and expression of the Wnt target genes intercellular adhesion molecule 1 (ICAM-1) and vascular endothelial growth factor (VEGF). Uric acid (UA), a PN scavenger, and 5,10,15,20-Tetrakis (4-sulfonatophenyl) porphyrinato Iron III Chloride (FeTPPS), a PN decomposition catalyst, suppressed Wnt signaling and ICAM-1 and VEGF overexpression induced by PN, HNE, and HG. Furthermore, UA and FeTPPS also inhibited Wnt signaling induced by the Wnt ligand. In streptozotocin-induced diabetic rats, retinal levels of 3-NT, β-catenin, nuclear β-catenin, pLRP6, VEGF, and ICAM-1 were markedly increased. UA treatment for 6 weeks ameliorated diabetes-induced Wnt signaling in the diabetic rat retina. The UA treatment also decreased inflammatory cell infiltration and extraverted serum albumin in the perfused retina of diabetic rats, suggesting decreased retinal inflammation and vascular leakage. Innovation and Conclusion: Nitrosative stress in diabetes contributes to Wnt pathway activation in the retina, and Wnt signaling may mediate the pathogenic effects of nitrosative stress in DR. Antioxid. Redox Signal. 18, 1141–1153.
PMCID: PMC3579458  PMID: 23066786
12.  Fus1/Tusc2 Is a Novel Regulator of Mitochondrial Calcium Handling, Ca2+-Coupled Mitochondrial Processes, and Ca2+-Dependent NFAT and NF-κB Pathways in CD4+ T Cells 
Antioxidants & Redox Signaling  2014;20(10):1533-1547.
Aims: Fus1 has been established as mitochondrial tumor suppressor, immunomodulator, and antioxidant protein, but molecular mechanism of these activities remained to be identified. Based on putative calcium-binding and myristoyl-binding domains that we identified in Fus1, we explored our hypothesis that Fus1 regulates mitochondrial calcium handling and calcium-coupled processes. Results: Fus1 loss resulted in reduced rate of mitochondrial calcium uptake in calcium-loaded epithelial cells, splenocytes, and activated CD4+ T cells. The reduced rate of mitochondrial calcium uptake in Fus1-deficient cells correlated with cytosolic calcium increase and dysregulation of calcium-coupled mitochondrial parameters, such as reactive oxygen species production, ΔμH+, mitochondrial permeability transition pore opening, and GSH content. Inhibition of calcium efflux via mitochondria, Na+/Ca2+ exchanger significantly improved the mitochondrial calcium uptake in Fus1−/− cells. Ex vivo analysis of activated CD4+ T cells showed Fus1-dependent changes in calcium-regulated processes, such as surface expression of CD4 and PD1/PD-L1, proliferation, and Th polarization. Fus1−/− T cells showed increased basal expression of calcium-dependent NF-κB and NFAT targets but were unable to fully activate these pathways after stimulation. Innovation: Our results establish Fus1 as one of the few identified regulators of mitochondrial calcium handling. Our data support the idea that alterations in mitochondrial calcium dynamics could lead to the disruption of metabolic coupling in mitochondria that, in turn, may result in multiple cellular and systemic abnormalities. Conclusion: Our findings suggest that Fus1 achieves its protective role in inflammation, autoimmunity, and cancer via the regulation of mitochondrial calcium and calcium-coupled parameters. Antioxid. Redox Signal. 20, 1533–1547.
PMCID: PMC3942676  PMID: 24328503
13.  FUsed in Sarcoma Is a Novel Regulator of Manganese Superoxide Dismutase Gene Transcription 
Antioxidants & Redox Signaling  2014;20(10):1550-1566.
Aims: FUsed in sarcoma (FUS) is a multifunctional DNA/RNA-binding protein that possesses diverse roles, such as RNA splicing, RNA transport, DNA repair, translation, and transcription. The network of enzymes and processes regulated by FUS is far from being fully described. In this study, we have focused on the mechanisms of FUS-regulated manganese superoxide dismutase (MnSOD) gene transcription. Results: Here we demonstrate that FUS is a component of the transcription complex that regulates the expression of MnSOD. Overexpression of FUS increased MnSOD expression in a dose-dependent manner and knockdown of FUS by siRNA led to the inhibition of MnSOD gene transcription. Reporter analyses, chromatin immunoprecipitation assay, electrophoretic mobility shift assay, affinity chromatography, and surface plasmon resonance analyses revealed the far upstream region of MnSOD promoter as an important target of FUS-mediated MnSOD transcription and confirmed that FUS binds to the MnSOD promoter and interacts with specificity protein 1 (Sp1). Importantly, overexpression of familial amyotropic lateral sclerosis (fALS)-linked R521G mutant FUS resulted in a significantly reduced level of MnSOD expression and activity, which is consistent with the decline in MnSOD activity observed in fibroblasts from fALS patients with the R521G mutation. R521G-mutant FUS abrogates MnSOD promoter-binding activity and interaction with Sp1. Innovation and Conclusion: This study identifies FUS as playing a critical role in MnSOD gene transcription and reveals a previously unrecognized relationship between MnSOD and mutant FUS in fALS. Antioxid. Redox Signal. 20, 1550–1566.
PMCID: PMC3942683  PMID: 23834335
14.  Hydrogen Peroxide Sensing and Signaling by Protein Kinases in the Cardiovascular System 
Antioxidants & Redox Signaling  2013;18(9):1042-1052.
Significance: Oxidants were once principally considered perpetrators of injury and disease. However, this has become an antiquated view, with cumulative evidence showing that the oxidant hydrogen peroxide serves as a signaling molecule. Hydrogen peroxide carries vital information about the redox state of the cell and is crucial for homeostatic regulation during health and adaptation to stress. Recent Advances: In this review, we examine the contemporary concepts for how hydrogen peroxide is sensed and transduced into a biological response by introducing post-translational oxidative modifications on select proteins. Oxidant sensing and signaling by kinases are of particular importance as they integrate oxidant signals into phospho-regulated pathways. We focus on CAMKII, PKA, and PKG, kinases whose redox regulation has notable impact on cardiovascular function. Critical Issues: In addition, we examine the mechanism for regulating intracellular hydrogen peroxide, considering the net concentrations that may accumulate. The effects of endogenously generated oxidants are often modeled by applying exogenous hydrogen peroxide to cells or tissues. Here we consider whether model systems exposed to exogenous hydrogen peroxide have relevance to systems where the oxidant is generated endogenously, and if so, what concentration can be justified in terms of relevance to health and disease. Future Directions: Improving our understanding of hydrogen peroxide signaling and the sensor proteins that it can modify will help us develop new strategies to regulate intracellular signaling to prevent disease. Antioxid. Redox Signal. 18, 1042–1052.
PMCID: PMC3567777  PMID: 22867279
15.  Interacting with Thioredoxin-1—Disease or No Disease? 
Antioxidants & Redox Signaling  2013;18(9):1053-1062.
Significance: Many cardiovascular disorders are accompanied by a deregulated cellular redox balance resulting in elevated levels of intracellular reactive oxygen species (ROS). One major antioxidative cellular molecule is thioredoxin-1 (Trx-1). Its indispensability is demonstrated by the embryonic lethality of Trx-1 deficient mice. Trx-1 is ubiquitously expressed in cells and has numerous, diverse functions. It not only reduces oxidized proteins or, together with peroxiredoxins, detoxifies H2O2, but also binds to several proteins and thereby regulates their functions. The interaction partners of Trx-1 differ depending on its localization in the cytosol or in the nucleus. Recent Advances/Critical Issues: Over the past decade it has become clear that Trx-1 is not only critical for tumor functions, which has resulted in therapeutic approaches targeting this protein, but also essential for proper functions of the vasculature and the heart. Changes in post-translational modifications of Trx-1 or in its interactions with other proteins can lead to a switch from a physiologic state of cells and organs to diverse pathologies. This review provides insights into the role of Trx-1 in different physiological situations and cardiac hypertrophy, ischemia reperfusion injury, heart failure, atherosclerosis, and diabetes mellitus type 2, underscoring the central role of Trx-1 in cardiovascular health and disease. Future Directions: Thus, the manipulation of Trx-1 activity in the heart and/or vasculature, for example, by small molecules, seems to be a promising therapeutic option in cardiovascular diseases, as general anti-oxidant treatments would not take into account interactions of Trx-1 with other proteins and also eliminate vital ROS. Antioxid. Redox Signal. 18, 1053–1062.
PMCID: PMC3567779  PMID: 22867430
16.  NADPH Oxidases in Heart Failure: Poachers or Gamekeepers? 
Antioxidants & Redox Signaling  2013;18(9):1024-1041.
Significance: Oxidative stress is involved in the pathogenesis of heart failure but clinical antioxidant trials have been unsuccessful. This may be because effects of reactive oxygen species (ROS) depend upon their source, location, and concentration. Nicotinamide adenine dinucleotide phosphate oxidase (Nox) proteins generate ROS in a highly regulated fashion and modulate several components of the heart failure phenotype. Recent Advances: Two Nox isoforms, Nox2 and Nox4, are expressed in the heart. Studies using gene-modified mice deficient in Nox2 activity indicate that Nox2 activation contributes to angiotensin II–induced cardiomyocyte hypertrophy, atrial fibrillation, and the development of interstitial fibrosis but may also positively modulate physiological excitation-contraction coupling. Nox2 contributes to myocyte death under stress situations and plays important roles in postmyocardial infarction remodeling, in part by modulating matrix metalloprotease activity. In contrast to Nox2, Nox4 is constitutively active at a low level and induces protective effects in the heart under chronic stress, for example, by maintaining myocardial capillary density. However, high levels of Nox4 could have detrimental effects. Critical Issues: The effects of Nox proteins during the development of heart failure likely depend upon the isoform, activation level, and cellular distribution, and may include beneficial as well as detrimental effects. More needs to be learnt about the precise regulation of abundance and biochemical activity of these proteins in the heart as well as the downstream signaling pathways that they regulate. Future Directions: The development of specific approaches to target individual Nox isoforms and/or specific cell types may be important for the achievement of therapeutic efficacy in heart failure. Antioxid. Redox Signal. 18, 1024–1041.
PMCID: PMC3567780  PMID: 22747566
17.  Reductive Stress Linked to Small HSPs, G6PD, and Nrf2 Pathways in Heart Disease 
Antioxidants & Redox Signaling  2013;18(9):1114-1127.
Significance: Aerobic organisms must exist between the dueling biological metabolic processes for energy and respiration and the obligatory generation of reactive oxygen species (ROS) whose deleterious consequences can reduce survival. Wide fluctuations in harmful ROS generation are circumvented by endogenous countermeasures (i.e., enzymatic and nonenzymatic antioxidants systems) whose capacity decline with aging and are enhanced by disease states. Recent Advances: Substantial efforts on the cellular and molecular underpinnings of oxidative stress has been complemented recently by the discovery that reductive stress similarly predisposes to inheritable cardiomyopathy, firmly establishing that the biological extremes of the redox spectrum play essential roles in disease pathogenesis. Critical Issues: Because antioxidants by nutritional or pharmacological supplement to prevent or mitigate disease states have been largely disappointing, we hypothesize that lack of efficacy of antioxidants might be related to adverse outcomes in responders at the reductive end of the redox spectrum. As emerging concepts, such as reductive, as opposed, oxidative stress are further explored, there is an urgent and critical gap for biochemical phenotyping to guide the targeted clinical applications of therapeutic interventions. Future Directions: New approaches are vitally needed for characterizing redox states with the long-term goal to noninvasively assess distinct clinical states (e.g., presymptomatic, end-stage) with the diagnostic accuracy to guide personalized medicine. Antioxid. Redox Signal. 18, 1114–1127.
PMCID: PMC3567781  PMID: 22938199
18.  Nitric Oxide Synthases in Heart Failure 
Antioxidants & Redox Signaling  2013;18(9):1078-1099.
Significance: The regulation of myocardial function by constitutive nitric oxide synthases (NOS) is important for the maintenance of myocardial Ca2+ homeostasis, relaxation and distensibility, and protection from arrhythmia and abnormal stress stimuli. However, sustained insults such as diabetes, hypertension, hemodynamic overload, and atrial fibrillation lead to dysfunctional NOS activity with superoxide produced instead of NO and worse pathophysiology. Recent Advances: Major strides in understanding the role of normal and abnormal constitutive NOS in the heart have revealed molecular targets by which NO modulates myocyte function and morphology, the role and nature of post-translational modifications of NOS, and factors controlling nitroso-redox balance. Localized and differential signaling from NOS1 (neuronal) versus NOS3 (endothelial) isoforms are being identified, as are methods to restore NOS function in heart disease. Critical Issues: Abnormal NOS signaling plays a key role in many cardiac disorders, while targeted modulation may potentially reverse this pathogenic source of oxidative stress. Future Directions: Improvements in the clinical translation of potent modulators of NOS function/dysfunction may ultimately provide a powerful new treatment for many hearts diseases that are fueled by nitroso-redox imbalance. Antioxid. Redox Signal. 18, 1078–1099.
PMCID: PMC3567782  PMID: 22871241
19.  Angiogenesis in the Infarcted Myocardium 
Antioxidants & Redox Signaling  2013;18(9):1100-1113.
Significance: Proangiogenic therapy appeared a promising strategy for the treatment of patients with acute myocardial infarction (MI), as de novo formation of microvessels, has the potential to salvage ischemic myocardium at early stages after MI, and is also essential to prevent the transition to heart failure through the control of cardiomyocyte hypertrophy and contractility. Recent Advances: Exciting preclinical studies evaluating proangiogenic therapies for MI have prompted the initiation of numerous clinical trials based on protein or gene transfer delivery of growth factors and administration of stem/progenitor cells, mainly from bone marrow origin. Nonetheless, these clinical trials showed mixed results in patients with acute MI. Critical Issues: Even though methodological caveats, such as way of delivery for angiogenic growth factors (e.g., protein vs. gene transfer) and stem/progenitor cells or isolation/culture procedure for regenerative cells might partially explain the failure of such trials, it appears that delivery of a single growth factor or cell type does not support angiogenesis sufficiently to promote cardiac repair. Future Directions: Optimization of proangiogenic therapies might include stimulation of both angiogenesis and vessel maturation and/or the use of additional sources of stem/progenitor cells, such as cardiac progenitor cells. Experimental unraveling of the mechanisms of angiogenesis, vessel maturation, and endothelial cell/cardiomyocyte cross talk in the ischemic heart, analysis of emerging pathways, as well as a better understanding of how cardiovascular risk factors impact endogenous and therapeutically stimulated angiogenesis, would undoubtedly pave the way for the development of novel and hopefully efficient angiogenesis targeting therapeutics for the treatment of acute MI. Antioxid. Redox Signal. 18, 1100–1113.
PMCID: PMC3567783  PMID: 22870932
20.  Mass Spectrometry-Based Quantitative Proteomics for Dissecting Multiplexed Redox Cysteine Modifications in Nitric Oxide-Protected Cardiomyocyte Under Hypoxia 
Antioxidants & Redox Signaling  2014;20(9):1365-1381.
Aims: Distinctive states of redox-dependent cysteine (Cys) modifications are known to regulate signaling homeostasis under various pathophysiological conditions, including myocardial injury or protection in response to ischemic stress. Recent evidence further implicates a dynamic interplay among these modified forms following changes in cellular redox environment. However, a precise delineation of multiplexed Cys modifications in a cellular context remains technically challenging. To this end, we have now developed a mass spectrometry (MS)-based quantitative approach using a set of novel iodoacetyl-based Cys-reactive isobaric tags (irreversible isobaric iodoacetyl Cys-reactive tandem mass tag [iodoTMT]) endowed with unique irreversible Cys-reactivities. Results: We have established a sequential iodoTMT-switch procedure coupled with efficient immunoenrichment and advanced shotgun liquid chromatography-MS/MS analysis. This workflow allows us to differentially quantify the multiple redox-modified forms of a Cys site in the original cellular context. In one single analysis, we have identified over 260 Cys sites showing quantitative differences in multiplexed redox modifications from the total lysates of H9c2 cardiomyocytes experiencing hypoxia in the absence and presence of S-nitrosoglutathione (GSNO), indicative of a distinct pattern of individual susceptibility to S-nitrosylation or S-glutathionylation. Among those most significantly affected are proteins functionally implicated in hypoxic damage from which we showed that GSNO would protect. Innovation: We demonstrate for the first time how quantitative analysis of various Cys-redox modifications occurring in biological samples can be performed precisely and simultaneously at proteomic levels. Conclusion: We have not only developed a new approach to map global Cys-redoxomic regulation in vivo, but also provided new evidences implicating Cys-redox modifications of key molecules in NO-mediated ischemic cardioprotection. Antioxid. Redox Signal. 20, 1365–1381.
PMCID: PMC3936484  PMID: 24152285
21.  PTEN Phosphorylation and Nuclear Export Mediate Free Fatty Acid-Induced Oxidative Stress 
Antioxidants & Redox Signaling  2014;20(9):1382-1395.
Aim: Oxidative stress induced by free fatty acids (FFA) contributes to metabolic syndrome-associated development of cardiovascular diseases, yet molecular mechanisms remain poorly understood. This study aimed at establishing whether phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and its subcellular location play a role in FFA-induced endothelial oxidative stress. Results: Exposing human endothelial cells (ECs) with FFA activated mammalian target of rapamycin (mTOR)/S6K pathway, and upon activation, S6K directly phosphorylated PTEN at S380. Phosphorylation of PTEN increased its interaction with its deubiquitinase USP7 in the nucleus, leading to PTEN deubiquitination and nuclear export. The reduction of PTEN in the nucleus, in turn, decreased p53 acetylation and transcription, reduced the expression of the p53 target gene glutathione peroxidase-1 (GPX1), resulting in reactive oxygen species (ROS) accumulation and endothelial damage. Finally, C57BL/6J mice fed with high-fat atherogenic diet (HFAD) showed PTEN nuclear export, decreased p53 and GPX1 protein expressions, elevated levels of ROS, and significant lesions in aortas. Importantly, inhibition of mTOR or S6K effectively blocked these effects, suggesting that mTOR/S6K pathway mediates HFAD-induced oxidative stress and vascular damage via PTEN/p53/GPX1 inhibition in vivo. Innovation: Our study demonstrated for the first time that S6K directly phosphorylated PTEN at S380 under high FFA conditions, and this phosphorylation mediated FFA-induced endothelial oxidative stress. Furthermore, we showed that S380 phosphorylation affected PTEN monoubiquitination and nuclear localization, providing the first example of coordinated regulation of PTEN nuclear localization via phosphorylation and ubiquitination. Conclusion: Our studies provide a novel mechanism by which hyperlipidemia causes vascular oxidative damage through the phosphorylation of PTEN, blocking of PTEN nuclear function, and inhibition of p53/GPX1 activity. Antioxid. Redox Signal. 20, 1382–1395.
PMCID: PMC3936505  PMID: 24063548
22.  Iron-Targeting Antitumor Activity of Gallium Compounds and Novel Insights Into Triapine®-Metal Complexes 
Antioxidants & Redox Signaling  2013;18(8):956-972.
Significance: Despite advances made in the treatment of cancer, a significant number of patients succumb to this disease every year. Hence, there is a great need to develop new anticancer agents. Recent Advances: Emerging data show that malignant cells have a greater requirement for iron than normal cells do and that proteins involved in iron import, export, and storage may be altered in cancer cells. Therefore, strategies to perturb these iron-dependent steps in malignant cells hold promise for the treatment of cancer. Recent studies show that gallium compounds and metal-thiosemicarbazone complexes inhibit tumor cell growth by targeting iron homeostasis, including iron-dependent ribonucleotide reductase. Chemical similarities of gallium(III) with iron(III) enable the former to mimic the latter and interpose itself in critical iron-dependent steps in cellular proliferation. Newer gallium compounds have emerged with additional mechanisms of action. In clinical trials, the first-generation-compound gallium nitrate has exhibited activity against bladder cancer and non-Hodgkin's lymphoma, while the thiosemicarbazone Triapine® has demonstrated activity against other tumors. Critical Issues: Novel gallium compounds with greater cytotoxicity and a broader spectrum of antineoplastic activity than gallium nitrate should continue to be developed. Future Directions: The antineoplastic activity and toxicity of the existing novel gallium compounds and thiosemicarbazone-metal complexes should be tested in animal tumor models and advanced to Phase I and II clinical trials. Future research should identify biologic markers that predict tumor sensitivity to gallium compounds. This will help direct gallium-based therapy to cancer patients who are most likely to benefit from it. Antioxid. Redox Signal. 00, 000–000.
PMCID: PMC3557436  PMID: 22900955
23.  Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection 
Antioxidants & Redox Signaling  2013;18(8):899-929.
Significance: Anthracyclines (doxorubicin, daunorubicin, or epirubicin) rank among the most effective anticancer drugs, but their clinical usefulness is hampered by the risk of cardiotoxicity. The most feared are the chronic forms of cardiotoxicity, characterized by irreversible cardiac damage and congestive heart failure. Although the pathogenesis of anthracycline cardiotoxicity seems to be complex, the pivotal role has been traditionally attributed to the iron-mediated formation of reactive oxygen species (ROS). In clinics, the bisdioxopiperazine agent dexrazoxane (ICRF-187) reduces the risk of anthracycline cardiotoxicity without a significant effect on response to chemotherapy. The prevailing concept describes dexrazoxane as a prodrug undergoing bioactivation to an iron-chelating agent ADR-925, which may inhibit anthracycline-induced ROS formation and oxidative damage to cardiomyocytes. Recent Advances: A considerable body of evidence points to mitochondria as the key targets for anthracycline cardiotoxicity, and therefore it could be also crucial for effective cardioprotection. Numerous antioxidants and several iron chelators have been tested in vitro and in vivo with variable outcomes. None of these compounds have matched or even surpassed the effectiveness of dexrazoxane in chronic anthracycline cardiotoxicity settings, despite being stronger chelators and/or antioxidants. Critical Issues: The interpretation of many findings is complicated by the heterogeneity of experimental models and frequent employment of acute high-dose treatments with limited translatability to clinical practice. Future Directions: Dexrazoxane may be the key to the enigma of anthracycline cardiotoxicity, and therefore it warrants further investigation, including the search for alternative/complementary modes of cardioprotective action beyond simple iron chelation. Antioxid. Redox Signal. 00, 000–000.
PMCID: PMC3557437  PMID: 22794198
24.  Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications 
Antioxidants & Redox Signaling  2013;18(8):930-955.
Significance: Iron and topoisomerases are abundant and essential cellular components. Iron is required for several key processes such as DNA synthesis, mitochondrial electron transport, synthesis of heme, and as a co-factor for many redox enzymes. Topoisomerases serve as critical enzymes that resolve topological problems during DNA synthesis, transcription, and repair. Neoplastic cells have higher uptake and utilization of iron, as well as elevated levels of topoisomerase family members. Separately, the chelation of iron and the cytotoxic inhibition of topoisomerase have yielded potent anticancer agents. Recent Advances: The chemotherapeutic drugs doxorubicin and dexrazoxane both chelate iron and target topoisomerase 2 alpha (top2α). Newer chelators such as di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone and thiosemicarbazone -24 have recently been identified as top2α inhibitors. The growing list of agents that appear to chelate iron and inhibit topoisomerases prompts the question of whether and how these two distinct mechanisms might interplay for a cytotoxic chemotherapeutic outcome. Critical Issues: While iron chelation and topoisomerase inhibition each represent mechanistically advantageous anticancer therapeutic strategies, dual targeting agents present an attractive multi-modal opportunity for enhanced anticancer tumor killing and overcoming drug resistance. The commonalities and caveats of dual inhibition are presented in this review. Future Directions: Gaps in knowledge, relevant biomarkers, and strategies for future in vivo studies with dual inhibitors are discussed. Antioxid. Redox Signal. 00, 000–000.
PMCID: PMC3557438  PMID: 22900902
25.  Biological and Therapeutic Relevance of Nonreplicative DNA Polymerases to Cancer 
Antioxidants & Redox Signaling  2013;18(8):851-873.
Apart from surgical approaches, the treatment of cancer remains largely underpinned by radiotherapy and pharmacological agents that cause damage to cellular DNA, which ultimately causes cancer cell death. DNA polymerases, which are involved in the repair of cellular DNA damage, are therefore potential targets for inhibitors for improving the efficacy of cancer therapy. They can be divided, according to their main function, into two groups, namely replicative and nonreplicative enzymes. At least 15 different DNA polymerases, including their homologs, have been discovered to date, which vary considerably in processivity and fidelity. Many of the nonreplicative (specialized) DNA polymerases replicate DNA in an error-prone fashion, and they have been shown to participate in multiple DNA damage repair and tolerance pathways, which are often aberrant in cancer cells. Alterations in DNA repair pathways involving DNA polymerases have been linked with cancer survival and with treatment response to radiotherapy or to classes of cytotoxic drugs routinely used for cancer treatment, particularly cisplatin, oxaliplatin, etoposide, and bleomycin. Indeed, there are extensive preclinical data to suggest that DNA polymerase inhibition may prove to be a useful approach for increasing the effectiveness of therapies in patients with cancer. Furthermore, specialized DNA polymerases warrant examination of their potential use as clinical biomarkers to select for particular cancer therapies, to individualize treatment for patients. Antioxid. Redox Signal. 00, 000–000.
I. Introduction
II. Biochemistry and Molecular Biology of Nonreplicative DNA Polymerases
A. X family polymerases
1. DNA polymerase beta
2. DNA polymerase lambda
3. DNA polymerase mu
B. Y family polymerases
1. TLS pathways
2. DNA polymerase eta
3. DNA polymerase iota
4. DNA polymerase kappa
C. A family polymerases
1. DNA polymerase theta
D. B family polymerases
1. DNA polymerase zeta
III. Biological Relevance of Nonreplicative DNA Polymerases to Carcinogenesis
A. X family polymerases
B. Y family polymerases
C. A and B family polymerases
IV. The Potential Role of Nonreplicative DNA Polymerases in Cancer Treatment
A. Involvement of DNA polymerases in cellular responses to chemotherapy
B. The role of nonreplicative polymerases in cellular responses to radiotherapy
C. Targeting specialized DNA polymerases to improve cancer treatment
V. Conclusions
PMCID: PMC3557440  PMID: 22794079

Results 1-25 (556)