caa a22 4500 397574436 CHVBK 20180308164851.0 cr unu---uuuuu 161202e199602 xx s 000 0 eng 10.1093/hmg/5.2.283 doi (NATIONALLICENCE)oxford-10.1093/hmg/5.2.283 Elevation in the Ratio of Cu/Zn-Superoxide Dismutase to Glutathione Peroxidase Activity Induces Features of Cellular Senescence and This Effect Is Mediated by Hydrogen Peroxide [Elektronische Daten] [Judy B. de Haan, Francesca Cristiano, Rocco Iannello, Cecile Bladier, Michael J. Kelner, Ismail Kola] Although reactive oxygen species have been proposed to play a major role in the aging process, the exact molecular mechanisms remain elusive. In this study we investigate the effects of a perturbation in the ratio of Cu/Zn-superoxide dismutase activity (Sod1 dismutases .O2−to H2C2) to glutathione peroxidase activity (Gpx1 catalyses H2O2 conversion to H2O) on cell growth and development. Our data demonstrate that Sod1 transfected cell lines that have an elevation in the ratio of Sod1 activity to Gpx1 activity produce higher levels of H2O2 and exhibit well characterised markers of cellular senescence viz. slower proliferation and altered morphology. On the contrary, Sod1 transfected cell lines that have an unaltered ratio in the activity of these two enzymes, have unaltered levels of H2O2 and fail to show characteristics of senescence. Furthermore, fibroblasts established from individuals with Down syndrome have an increase in the ratio of Sod1 to Gpx1 activity compared with corresponding controls and senesce earlier. Interestingly, cells treated with H2O2 also show features of senescence and/or senesce earlier. We also show that Cip1 mRNA levels are elevated in Down syndrome cells, Sod1 transfectants with an altered Sod1 to Gpx1 activity ratio and those treated with H2O2, thus suggesting that the slow proliferation may be mediated by Cip1. Furthermore, our data demonstrate that Cip1 mRNA levels are induced by exposure of cells to H2O2. These data give valuable insight into possible molecular mechanisms that contribute to cellular senescence and may be useful in the evolution of therapeutic strategies for aging. © 1996 Oxford University Press de Haan Judy B. Molecular Genetics and Development Group, Institute of Reproduction and Development, Monash University, Clayton, Victoria 3168, Australia aut Cristiano Francesca Molecular Genetics and Development Group, Institute of Reproduction and Development, Monash University, Clayton, Victoria 3168, Australia aut Iannello Rocco Molecular Genetics and Development Group, Institute of Reproduction and Development, Monash University, Clayton, Victoria 3168, Australia aut Bladier Cecile Commissariat a l'Energie Atomique, Centre de Cadarache, Laboratoire de Phytotechnologie, 13108 St-Paul-lez-Durance, France aut Kelner Michael J. Department of Pathology, University of California, 200 West Arbor Drive, San Diego, California 92103-8320, USA aut Kola Ismail Molecular Genetics and Development Group, Institute of Reproduction and Development, Monash University, Clayton, Victoria 3168, Australia aut Human Molecular Genetics Oxford University Press 5/2(1996-02), 283-292 0964-6906 5:2<283 1996 5 hmg https://doi.org/10.1093/hmg/5.2.283 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1093/hmg/5.2.283 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- de Haan Judy B. Molecular Genetics and Development Group, Institute of Reproduction and Development, Monash University, Clayton, Victoria 3168, Australia aut NATIONALLICENCE 700 1- Cristiano Francesca Molecular Genetics and Development Group, Institute of Reproduction and Development, Monash University, Clayton, Victoria 3168, Australia aut NATIONALLICENCE 700 1- Iannello Rocco Molecular Genetics and Development Group, Institute of Reproduction and Development, Monash University, Clayton, Victoria 3168, Australia aut NATIONALLICENCE 700 1- Bladier Cecile Commissariat a l'Energie Atomique, Centre de Cadarache, Laboratoire de Phytotechnologie, 13108 St-Paul-lez-Durance, France aut NATIONALLICENCE 700 1- Kelner Michael J. Department of Pathology, University of California, 200 West Arbor Drive, San Diego, California 92103-8320, USA aut NATIONALLICENCE 700 1- Kola Ismail Molecular Genetics and Development Group, Institute of Reproduction and Development, Monash University, Clayton, Victoria 3168, Australia aut NATIONALLICENCE 773 0- Human Molecular Genetics Oxford University Press 5/2(1996-02), 283-292 0964-6906 5:2<283 1996 5 hmg Metadata rights reserved CC BY-NC-4.0 http://creativecommons.org/licenses/by-nc/4.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-oxford