The superoxide radical (O 2 − ) has long been considered a major cause of aging. O 2 − in cytosolic, extracellular, and mitochondrial pools is detoxified by dedicated superoxide dismutase (SOD) isoforms. We tested the impact of each SOD isoform in Caenorhabditis elegans by manipulating its five sod genes and saw no major effects on life span. sod genes are not required for daf-2 insulin/ IGF-1 receptor mutant longevity. However, loss of the extracellular Cu/ZnSOD sod-4 enhances daf-2 longevity and constitutive diapause, suggesting a signaling role for sod-4. Overall, these findings imply that O 2 − is not a major determinant of aging in C. elegans.Supplemental material is available at http://www.genesdev.org.Received April 11, 2008; revised version accepted September 29, 2008. Many forms of pathology lead to elevated levels of damage to biological macromolecules (Halliwell and Gutteridge 2007). This is also true of aging, the poorly understood biological process that leads to progressive deterioration and death. One strategy to discover the underlying mechanisms of aging has been to seek the causes of its associated molecular damage. An important early theory, proposed by Harman (1956), postulates that the cause might be oxygen free radicals. Harman later developed the theory, proposing a central role for the superoxide (O 2 − ) radical, issuing from the mitochondrial electron transport chain (Harman 1972). During the last few decades, much effort has been invested in tests of this nexus of theories (for review, see Muller et al. 2007 (Fujii et al. 1998). Two mitochondrial MnSOD isoforms are encoded by sod-2 and sod-3 (Giglio et al. 1994;Suzuki et al. 1996;Hunter et al. 1997).This superabundance of SOD isoforms has been a technical hurdle to investigations of the role of SOD and O 2 − in aging in C. elegans, and some of the sod genes have been barely studied. In situ gel SOD activity assays of a sod-1 deletion mutant imply that this gene encodes the major cytosolic Cu/ZnSOD (Jensen and Culotta 2005), leaving the function of sod-5 unclear. sod-3 mRNA levels are elevated in the dauer larva (Honda and Honda 1999), suggesting that this gene may play a special role in antioxidant defense in this long-lived, stress-resistant diapausal stage, but the role of sod-2 has remained obscure. In this study, we describe in detail the function of each of the five sod genes, characterizing their expression, and the phenotypic effects of manipulating their expression. This has allowed us to assess the effect on life history, especially aging, of each of the three major O 2 − pools, thereby critically testing the role of SOD and, by inference, O 2 − , in longevity assurance and aging. O 2 − can affect living organisms in a variety of ways. It can cause molecular damage that might contribute to aging; thus, one expectation of our study was that lowering SOD activity and increasing O 2 − levels might accelerate aging, and vice versa. H 2 O 2 derived from O 2 − can also act a secondary messenger-for example, in receptor tyrosine ...
Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) regulates cell proliferation and survival by extracellular interaction and inactivation of the growth factor IGF-I. Beyond that, IGF-independent actions mediated by intracellular IGFBP-3 including nuclear-IGFBP-3, have also been described. We here show, using both confocal and electron microscopy and cell fractionation, that the extracellular addition of IGFBP-3 to living cells results in rapid uptake and nuclear delivery of IGFBP-3, by yet partly unknown mechanisms. IGFBP-3 is internalized through a dynamin-dependent pathway, traffics through endocytic compartments and is finally delivered into the nucleus. We observed docking of IGFBP-3 containing structures to the nuclear envelope and found IGFBP-3 containing dot-like structures to permeate the nuclear envelope. In summary, our findings establish the pathway by which this tumor suppressor protein is delivered from extracellular space to the nucleus.
IGF-binding protein-3 (IGFBP-3) is a modulator of the IGF-signaling pathway and was described as an anti-cancer agent in prostate cancer. The molecular mechanisms underlying these effects remained, however, largely undefined. We analyzed the influence of recombinant IGFBP-3 on cell proliferation of PC3, Du145, and LNCaP prostate cancer cells. As expected, IGFBP-3 inhibited IGF-stimulated cell proliferation by blocking IGF-mediated proliferation signals, but we observed an IGF-independent inhibitory effect of IGFBP-3 on prostate cancer cell proliferation in long-term cultures. We further investigated the influence of IGFBP-3 on adhesion, motility, and invasion of prostate cancer cells using adhesion assays, live-cell imaging techniques, and matrigel invasion measurements. There was a clear inhibitory effect of IGFBP-3 on tumor cell adhesion to extracellular matrix components in the presence and absence of IGF, whereas cell-cell adhesion was not affected. The same inhibitory effect of IGFBP-3 was determined on cell motility when realtime cell movements were followed. In addition, IGFBP-3 was able to inhibit tumor cell invasion through matrigel. In summary, we show that IGFBP-3 inhibits proliferation, adhesion, migration, and invasion processes of prostate tumor cells. These newly described mechanisms of IGFBP-3 can be of importance for tumor progression and support a role of IGFBP-3 in therapeutic settings.
Background: Phytoestrogens are a diverse group of non-steroidal plant compounds. Because they have chemical structures similar to estrogens they are able to bind on estrogen receptors in humans. Objectives: In this study, we tested the effects of crude phytoestrogen extracts from rye (Secale cereale), green pea (Pisum sativum) and yellow pea seeds (Pisum sativum cv.) on cell proliferation and the production of progesterone in trophoblast tumor cells of the cell line Jeg3. Methods: Isoflavone extracts from green and yellow pea seeds and lignan extracts from rye seeds were obtained, using different extraction methods. Isolated extracts were incubated in different concentrations with trophoblast tumor cells. Untreated cells were used as controls. At designated times, aliquots were removed and tested for estradiol and progesterone production. In addition, we tested the effects of the phytoestrogen extracts on cell proliferation. Results: Cell proliferation is significantly inhibited by potential phytoestrogens isolated from rye, green and yellow pea seeds in trophoblast tumor cells of the cell line Jeg3. We found a correlation between the effects of proliferation and production of estradiol in isoflavone extracts from green and yellow pea seeds in Jeg3 cells. In addition, higher concentrations of isoflavones isolated from green pea seeds and lignans from rye showed also a inhibition of progesterone production whereas higher concentrations of rye lignans elevated estradiol production in Jeg3 cells. Conclusion: A useful indicator test system for potential phytoestrogens could be established. Based on the obtained results it is proposed that green and yellow pea seeds contain measurable concentrations of isoflavones and rye seeds contain lignans which can be isolated and used for special human diet programs.
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