Human Molecular Genetics, Vol 5, 283-292, Copyright © 1996 by Oxford University Press
JB de Haan, F Cristiano, R Iannello, C Bladier, MJ Kelner and I 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 H2O2) 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 tribute to cellular senescence and may
be useful in the evolution of therapeutic strategies for aging.
ARTICLES
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
Institute of Reproduction and Development, Monash University, Clayton, Victoria, Australia.
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