Regulation of mtDNA Expression

MtDNA transcription seems capable of responding to both local and global (system level) signals. A rationale for the latter is readily appreciated when one considers that proper mitochondrial function is dependent on the successful coordination of signals received by nuclear and mitochondrial genomes. Responsiveness can be tissue specific, as response to vitamin D though its metabolite la, 25-dihydroxyvitamin D3 la,25-(OH)2D3 differs in the kidney (mtDNA transcription decreases) and intestine...

Sensitivity Of Insulin Gene Promoter To Glycation And Oxidative Stress

Among reducing sugars that potentially induce glycation, D-ribose is outstanding for its very potent activity and thus is often used in in vitro studies as an inducer of glycation (Franklin and Higgins, 1981 Hasegawa et al., 1995). We therefore used D-ribose to evaluate the effects of glycation on insulin gene transcription (Matsuoka et al., 1997). According to the results of reporter gene analyses, the insulin gene promoter but not the 3-actin gene promoter or RSV-LTR promoter was sensitive to...

References

Ammendola, R., Mesuraca, M., Russo, T., and Cimino, F. (1994). The DNA-binding efficiency of Spl is affected by redox changes. Eur. J. Biochem. 225, 483-489. Beato, M. (1989). Gene regulation by steroid hormones. Cell (Cambridge, Mass.) 56, 335-344. Bender, K., Blattner, C., Knebel, A., Iordanov, M., Herrlich, P., and Rahmsdorf, H. J. (1997). UV-induced signal transduction. J. Photochem. Photobiol. B 37, 1-17. Berardini, M. D., Souhami, R. L., Lee, C. S., Gibson, N. W., Butler, J., and Hartley,...

Proapoptotic Properties Of Antioxidants

Apart from ROS-detoxifying effects, antioxidant molecules may function as regulators of signal transduction pathways. For example, the possibility that N-acetylcysteine, unlike other antioxidants, suppresses neuronal apoptosis by regulating cell cycle progression has been proposed (Ferrari et al., 1995). In several other cases, however, potentiation of apoptosis by antioxidants has been reported to occur by pathways that are apparently independent of ROS detoxification. N-Acetylcysteine has...

Ion Channels

No field in physiology, it seems, is more confusing than that of electro-physiology, which has a language all to itself. Yet the past two decades have witnessed a massive increase in our understanding of ion channels and in our ability to identify their molecular makeup and their biophysical behavior. As the role of ion channels in signal transduction and cell physiology has been progressively elucidated, so too has the modulation of channel function by oxidation reduction reactions. The...

Rac And Respiratory Burst In Phagocytes

In phagocytic cells, Rac induces activation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase leading to free radical production. Intracellular pathways leading to the generation of ROS are best characterized in these specialized cells. The superoxide-free radical (02' ) is generated by the multimolecular NADPH oxidase complex, which includes Rac (Abo etal., 1991 Bokoch, 1994 Jones, 1994 Knaus etal., 1991). Rac was shown to stabilize the assembly of several proteins, to form...

Peroxiredoxins In Cell Signaling

Intracellular signaling pathways are complex networks that modulate nuclear gene expression. Intermediating proteins utilized in signal transduction are unmerous and incompletely understood. Kinases and phosphatases modify function by phosphorylation and dephosphorylation. Acetylases and deacetylases regulate activity by acetylation and deacetylation. Oxidants and antioxidants represent a different set of signal transducers that act through redox. Similar to other signaling events, redox can...

Mechanism of Peroxide Reduction

Peroxiredoxins have neither tightly bound metal ions nor prosthetic groups such as heme or flavin (Kim et al, 1988). The ability of peroxiredoxins to reduce peroxides is attributed to their cysteine residues. However, one peroxiredoxin, PAG, is a heme-binding protein (Immenschuh et al, 1995). On treatment of cells with a low concentration of hemin, the antioxidant activity of PAG is inhibited (Ishii et al, 1993). These observations suggest that heme binding is physiologically relevant to PAG...

Yoshitaka Kajimoto Yoshimitsu Yamasaki Takaaki Matsuoka Hideaki Kaneto and Masatsugu Hori

Department of Internal Medicine and Therapeutics (A8) Osaka University Graduate School of Medicine Suita 565-0871, Japan We have found that the insulin gene promoter is rather sensitive to oxidative stress caused by the induction of glycation. Results of reporter gene analyses using 3-cell-derived HIT-T15 cells revealed that approximately 50 and 80 of the insulin gene promoter activity was lost when the cells were kept for 3 days in the presence of 40 and 60 mM D-ribose, respectively. The...

Ionizing Radiation

Ionizing radiation is well known to kill cells via the induction of DNA damage. In animals, certain cell types are much more sensitive than others, and this difference in sensitivity is taken advantage of for radiation therapy of malignancies. For example, rapidly dividing cells are known to be sensitive. One of the most successful uses of radiation therapy is for the treatment of B-cell leukemia, followed by bone marrow transplantation. Studies have shown that ionizing radiation induces...

Gary L Schieven

Bristol-Myers Squibb Pharmaceutical Research Institute Princeton, New Jersey 08543 Oxidative stress has been shown to activate tyrosine phosphorylation signal transduction pathways in a wide variety of cell types. These pathways are normally under the control of ligand binding to receptors. Oxidative stress is able to bypass this normal receptor control to activate pathways that are often the central regulatory pathways for cellular proliferation and functional responses. Ionizing radiation,...

Mitochondrial Genome

Mammalian mitochondrial genomes are compact, double-stranded, circular DNAs that encode polypeptides that are constituents of the respiratory chain (see Fig. 1). The copy number appears tissue specific and highly variable, with estimates for cells containing mitochondria ranging from as few as four (platelets, Shuster et al., 1988) to as many as 7900 (HeLa cells King and Attardi, 1989). The mitochondrial genetic code is slightly different than that used by the nuclear genome. The human...

Microbial Peroxiredoxins

The complete genome sequences of a dozen bacteria and one yeast strain have been determined. This information has permitted a thorough comparison of microbial peroxiredoxins, yielding novel insights into the molecular evolution and the biology of these antioxidant enzymes. There are three peroxiredoxins in Escherichia coli. The alkyl hydroperoxide reductase colorless subunit (AhpC) is a prototype peroxiredoxin that reduces hydroperoxide using electrons transferred from AhpF, a thioredoxin...

Epidemiological Studies Showing Protective Effects of Antioxidants on Coronary Heart Disease in Humans

A number of studies (Table I) have investigated the relationship between plasma vitamin E concentrations or intakes and incidence of coronary heart disease. In 12 European populations of middle-aged men (40-59 years of age) with common plasma cholesterol (5.7-6.2 mmol liter) and blood pressure, both classical risk factors lacked significant correlation to ischemic heart disease mortality, whereas absolute levels of vitamin E showed a strong inverse correlation (r2 0.63, p 0.002). In all...

Molecular Mechanisms of Antioxidant Regulation

Because of the diverse chemical structure of the antioxidants, it is rather difficult to understand the exact mechanisms and sites of action of antioxidants downregulating agonist-induced cell adhesion Fig. 10 . Previous studies have suggested that activation of the agonist-induced transcription of cell adhesion molecules e.g., E-selectin, ICAM-1, and VCAM-1 in cells are dependent, at least in part, on the activation of redox-sensitive transcription factors NF-kB and AP-1 Marui et al., 1993...