The readings for each session are listed below. The required readings for each session are designated Paper 1 and Paper 2. All other readings are optional.
| SES # | TOPICS | OVERVIEW | READINGS |
|---|---|---|---|
| 2 | The high price of energy: Mitrochondrial production of ROS |
Paper 1The first paper describes mechanisms by which ROS are produced in the mitochondrial electron transport chain. | Chen, Q., E. J. Vazquez, S. Moghaddas, C. L. Hoppel, and E. J. Lesnefsky. "Production of Reactive Oxygen Species by Mitochondria: Central Role of Complex III." J Biol Chem 278 (2003): 36027-31. |
Paper 2The second paper discusses how coupling electron transfer to available oxygen affects ROS production. | Campian, J. L., M. Qian, X. Gao, and J. W. Eaton. "Oxygen Tolerance and Coupling of Mitochondrial Electron Transport." J Biol Chem 279 (2004): 46580-7. | ||
| 3 | Radical messengers: ROS as facilitators of cellular signaling |
Paper 1The first paper describes how ROS can affect the activity of protein tyrosine phosphatases (PTP), thus facilitating mitogenic signals in response to growth factors. | Meng, T. C., T. Fukada, and N. K. Tonks. "Reversible Oxidation and Inactivation of Protein Tyrosine Phosphatases in vivo." Mol Cell 9 (2002): 387-99. |
Paper 2The second paper provides an example of how modulating PTP function can regulate stress-responsive kinase pathways and programmed cell death (PCD). | Kamata, H., S. Honda, S. Maeda, L. Chang, H. Hirata, and M. Karin. "Reactive Oxygen Species Promote TNFalpha-induced Death and Sustained JNK Activation by Inhibiting MAP Kinase Phosphatases." Cell 120 (2005): 649-61. | ||
Suggested background for paper 1This is a very short review of paper 1. It gives an overview of what the issues addressed by the first papers are and why its results are important. | Dong, X., I. I. Rovira, and T. Finkel. "Oxidants Painting the Cysteine Chapel: Redox Regulation of PTPs." Dev Cell 2 (2002): 251-2. | ||
Suggested background for paper 2Another short review discussing the stress kinase pathways involved in ROS signaling. There is a very nice schematic of cross-talk between ROS and the proteins in these pathways. | Pham, C. G., S. Papa, C. Bubici, F. Zazzeroni, and G. Franzoso. "Oxygen JNKies: Phosphatases Overdose on ROS." Dev Cell 8 (2005): 452-4. | ||
| 4 | Hired assassins: ROS in anti-pathogen defense |
Paper 1The first paper follows up on the mechanism of ROS production in TNF-alpha-induced cell death, which was discussed as an example of ROS signaling last week. | Kim, Y. S., M. J. Morgan, S. Choksi, and Z. G. Liu. "TNF-induced Activation of the Nox1 NADPH Oxidase and its Role in the Induction of Necrotic Cell Death." Mol Cell 26 (2007): 675-87. |
Paper 2The second paper describes how the anti-microbial peptide histatin, found in saliva, uses ROS production as an essential step in killing Candida albicans, a type of fungus found in the mucous membranes of the mouth. | Helmerhorst, E. J., R. F. Troxler, and F. G. Oppenheim. "The Human Salivary Peptide Histatin 5 Exerts its Antifungal Activity Through the Formation of Reactive Oxygen Species." Proc Natl Acad Sci USA 98 (2001): 14637-42. | ||
Suggested background for paper 1A short review that summarizes the pathway linking ROS production by NADPH oxidases (Nox) and TNFalpha pathway. Also, please review figures 1, 2, 3 and 6 of paper 2 from Ses #3 - we will discuss these as a prelude to this week's paper. | Vanden Berghe, T., W. Declercq, and P. Vandenabeele. "NADPH Oxidases: New Players in TNF-induced Necrotic Cell Death." Mol Cell 26 (2007): 769-71. | ||
| 5 | Antioxidants: fighting the good fight |
Paper 1The first paper discusses the antioxidant benefits of a key ingredient of red wine, resveratrol. | Jang, M., L. Cai, G. O. Udeani, K. V. Slowing, C. F. Thomas, C. W. Beecher, and H. H. Fong, et al. "Cancer Chemopreventive Activity of Resveratrol, a Natural Product Derived from Grapes." Science 275 (1997): 218-20. |
Paper 2The second paper is a short one-page commentary about the benefits of dark chocolate over milk chocolate (samples will be provided). | Serafini, M., R. Bugianesi, G. Maiani, S. Valtuena, S. De Santis, and A. Crozier. "Plasma Antioxidants from Chocolate." Nature 424 (2003): 1013. | ||
Just for funA one-page nature commentary on the antioxidant properties of apples. | Eberhardt, M. V., C. Y. Lee, and R. H. Liu. "Antioxidant Activity of Fresh Apples." Nature 405 (2000): 903-4. | ||
Just for funAn interesting short commentary correlating cardiovascular health and longevity in parts of Europe with the antioxidant properties of the local wines. | Corder, R., W. Mullen, N. Q. Khan, S. C. Marks, E. G. Wood, M. J. Carrier, and A. Crozier. "Red Wine Procyanidins and Vascular Health." Nature 444 (2006): 566. | ||
| 6 | The free radical theory: ROS and aging |
Paper 1Today's two papers illustrate why Denham Harman's theory has been controversial. The first paper uses a mouse model to show that enhanced scavenging of mitochondrial H2O2 increases murine lifespan. | Trifunovic, A., A. Hansson, A. Wredenberg, A. T. Rovio, E. Dufour, I. Khvorostov, J. N. Spelbrink, R. Wibom, H. T. Jacobs, and N. G. Larsson. "Somatic mtDNA Mutations Cause Aging Phenotypes without Affecting Reactive Oxygen Species Production." Proc Natl Acad Sci USA 102 (2005): 17993-8. |
Paper 2The second paper uses a mouse model with elevated mitochondrial DNA mutation rates which does not show altered ROS levels. We will discuss these papers with a view to determining whether such disparate observations can somehow be reconciled. | Schriner, S. E., N. J. Linford, G. M. Martin, P. Treuting, C. E. Ogburn, M. Emond, and P. E. Coskun, et al. "Extension of Murine Life Span by Overexpression of Catalase Targeted to Mitochondria." Science 308 (2005): 1909-11. | ||
Suggested background for paper 2A previous paper by the authors of the second reading assignment - please read the abstract and the discussion. | Trefunovic, A., A. Wredenberg, M. Falkenberg, J. N. Spelbrink, A. T. Rovio, C. E. Bruder, and M. Bohlooly-Y, et al. "Premature Aging in Mice Expressing Defective Mitochondrial DNA Polymerase." Nature 429 (2004): 417-23. | ||
| 7 | The root of the problem: oxidative damage in stem cell renewal |
Paper 1The first paper shows that increased ROS affect HSC self-renewal capacity through activation of a stress signaling (p38 MAPK) pathway. | Ito, K., A. Hirao, F. Arai, K. Takubo, S. Matsuoka, K. Miyamoto, M. Ohmura, et al. "Reactive Oxygen Species Act Through p38 MAPK to Limit the Lifespan of Hematopoietic Stem Cells." Nat Med 12 (2006): 446-51. |
Paper 2The second paper utilizes a mouse model lacking an important enzyme that participates in endogenous DNA damage repair to show how mounting oxidative DNA damage during aging affects stem cell exhaustion. | Nijnik, A., L. Woodbine, C. Marchetti, S. Dawson, T. Lambe, C. Liu, and N. P. Rodrigues, et al. "DNA Repair is Limiting for Haematopoietic Stem Cells During Ageing." Nature 447 (2007): 686-90. | ||
Suggested background for paper 1A very short commentary on the role of H2O2 signaling in affecting cellular lifespan in hematopoietic stem cells. | Liu, J., and T. Finkel. "Stem Cell Aging: What Bleach can Teach." Nature Medicine 12 (2006): 383-4. | ||
| 8 | Balancing act: ROS effects on insulin resistance and diabetes |
Paper 1Today's papers highlight the exquisite balance needed in physiological ROS levels and how disruptions in this balance can tip the scale one way or the other when it comes to normal insulin signaling. | Houstis, N., E. D. Rosen, and E. S. Lander. "Reactive Oxygen Species have a Causal Role in Multiple Forms of Insulin Resistance." Nature 440 (2006): 944-8. |
Paper 2The second paper demonstrates the caveats of using antioxidant-based measures to treat symptoms of ROS-associated diseases. Sometimes, it's not a question of eliminating ROS but keeping them within physiologic levels. | McClung, J. P., C. A. Roneker, W. Mu, D. J. Lisk, P. Langlais, F. Liu, and X. G. Lei. "Development of Insulin Resistance and Obesity in Mice Overexpressing Cellular Glutathione Peroxidase." Proc Natl Acad Sci USA 101 (2004): 8852-7. | ||
Suggested readingThis is a paper by the same authors who conducted the studies on PTP signaling through ROS that we discussed in Ses #3. No need to read the whole paper, but it will be informative to read pp. 37716-37718 (omitting materials and methods). | Meng, T., D. A. Buckley, S. Galic, T. Tiganis, and N. K. Tonks. "Regulation of Insulin Signaling Through Reversible Oxidation of the Protein-tyrosine Phosphatases TC45 and PTP1B." J Biol Chem 279 (2004): 37716-25. | ||
| 9 | Breaking hearts: ROS in ischemic reperfusion injury |
Paper 1The first paper demonstrates that oxygen radicals are rapidly produced following reperfusion. | Zweier, J. L., J. T. Flaherty, and M. L. Weisfeldt. "Direct Measurement of Free Radical Generation following Reperfusion of Ischemic Myocardium." Proc Natl Acad Sci USA 84 (1987): 1404-7. |
Paper 2The second paper we will be discussing tests the effects of reperfusion in mice overexpressing the antioxidant enzyme, SOD1. | Dewald, O., N. G. Frangogiannis, M. Zoerlein, G. D. Duerr, C. Klemm, P. Knuefermann, and G. Taffet, et al. "Development of Murine Ischemic Cardiomyopathy is Associated with a Transient Inflammatory Reaction and Depends on Reactive Oxygen Species." Proc Natl Acad Sci USA 100 (2003): 2700-5. | ||
| 10 | Brain drain: oxidative stress in neurodegenerative diseases |
Paper 1The first paper describes a novel mechanism involving defective transcriptional regulation by which a major oxidative DNA damage lesion, 8-oxoguanine, affects age-related cognitive decline. | Lu, T., Y. Pan, S. Y. Kao, C. Li, I. Kohane, J. Chan, and B. A. Yankner. "Gene Regulation and DNA Damage in the Ageing Human Brain." Nature 429 (2004): 883-91. |
Paper 2The second paper highlights the complications of understanding whether increased ROS levels are the cause or the effect of disease phenotypes involving redox mechanisms. Bruijn, et al. show that the SOD1 mutations engender neurodegeneration through aggregated structures formed by the mutant protein and suggest that the observed ROS elevation is a side-effect rather than cause of the disease phenotype. | Bruijn, L. I., M. K. Houseweart, S. Kato, K. L. Anderson, S. D. Anderson, E. Ohama, A. G. Reaume, R. W. Scott, and D. W. Cleveland. "Aggregation and Motor Neuron Toxicity of an ALS-linked SOD1 Mutant Independent From Wild-type SOD1." Science 281 (1998): 1851-4. | ||
Suggested readingAn interesting counterpoint to paper 2 - a very short commentary summarizing what was believed about the role of ROS in ALS. | McNamara, J. O., and I Fridovich. "Did Radicals Strike Lou Gehrig?" Nature 362 (1993): 20-21. | ||
| 11 | Foot-soldiers of renegade cells: ROS in cancer and oncogenic transformation |
Paper 1The first paper we will discuss today elaborates on the role of aberrant signaling response to Ras-induced ROS in cellular transformation and evasion of senescence. | Dolado, I., A. Swat, N. Ajenjo, G. De Vita, A. Cuadrado, and A. R. Nebreda. "p38alpha MAP Kinase as a Sensor of Reactive Oxygen Species in Tumorigenesis." Cancer Cell 11 (2007): 191-205. |
Paper 2The second paper investigates how Rac1b, a downstream effector of Ras, uses ROS production to allow cancer cells to metastasize to other organs by a process called the epithelial-to-mesenchymal transition (EMT). | Radisky, D. C., D. D. Levy, L. E. Littlepage, H. Liu, C. M. Nelson, J. E. Fata, and D. Leake, et al. "Rac1b and Reactive Oxygen Species Mediate MMP-3-induced EMT and Genomic Instability." Nature 436 (2005): 123-7. | ||
Suggested reading for paper 1A very short perspective on the first paper we will be discussing. | Kennedy, N. J., C. Cellurale, and R. J. Davis. "A Radical Role for p38 MAPK in Tumor Initiation." Cancer Cell 11 (2007): 101-3. | ||
| 12 | Fighting fire with fire: more ROS or less ROS as therapeutic strategies? |
Paper 1The first paper describes the use of hydrogen gas to scavenge oxygen radicals in an animal model of brain reperfusion injury. | Ohsawa, I., M. Ishikawa, K. Takahashi, M. Watanabe, K. Nishimaki, K. Yamagata, K. Katsura, Y. Katayama, S. Asoh, and S. Ohta. "Hydrogen Acts as a Therapeutic Antioxidant by Selectively Reducing Cytotoxic Oxygen Radicals." Nat Med 14 (2007): 688-94. |
Paper 2The second paper discusses the utility of a ROS-inducing chemical in selectively destroying cancer cells, which already possess elevated ROS levels, over normal cells. As part of today's discussion, we will draw on what we have learned about the different roles of ROS in various pathologies to discuss why two such different strategies can both prove useful. | Trachootham, D., Y. Zhou, H. Zhang, Y. Demizu, Z. Chen, H. Pelicano, and P. J. Chiao, et al. "Selective Killing of Oncogenically Transformed Cells Through a ROS-mediated Mechanism by Beta-phenylethyl Isothiocyanate." Cancer Cell 10 (2006): 241-52. | ||
Suggested background for paper 2A short 1.5 page review discussing the role of increasing ROS as anticancer therapy. | Schumacker, P. T. "Reactive Oxygen Species in Cancer Cells: Live by the Sword, Die by the Sword." Cancer Cell 10 (2006): 175-176. |