The p66shc adaptor protein controls oxidative
stress response and life span in mammals
Enrica Migliaccio, Marco Giorgio, Simonetta Mele, Giuliana Pelicci,
Paolo Reboldi, Pier Paolo Pandolfi, Luisa Lanfrancone & Pier Giuseppe
Pelicci
Nature 402, 309-313 (1999).
Abstract
In mammals, the mechanisms that regulate stress response
are poorly understood and no genes are known to increase individual life
span. However, some gene mutations in invertebrates have been identified
that extend life span and enhance resistance to environmental stresses
such as ultraviolet light or reactive oxygen species (ROS). p66 is a splice
variant of p52shc/p46shc, a cytoplasmic signal transducer
involved in the transmission of mitogenic signals from activated receptors
to Ras. It becomes tyrosine phosphorylated upon activation of growth factor
receptors and forms stable complexes with Grb2, an adaptor protein for
the Ras exchange factor SOS. Since long life span is highly related with
oxidative stress response, so the author want to investigate the role of
p66shc in stress responses. In this paper, the author develope
the p66shc+/- and the p66shc-/- mice and report that
targeted mutation of the mouse p66shc gene induces stress resistance and
prolongs life span. The evidence include that p66shc is serine
phosphorylated upon treatment with hydrogen peroxide (H2O2)
or irradiation with ultraviolet light. Ablation of p66shc enhances cellular
resistance to apoptosis induced by H2O2 or ultraviolet
light and p66shc-/- mice have increased resistance to paraquat
and a 30% increase in life span. In addition, p53 and p21 stress response
is impaired in p66shc-/- cells.
References
1. Martin, G. M., Austad, S. N. & Johnson, T. E. Genetic analysis
of aging: role of
oxidative damage and environmental stresses. Nature Genet. 13,
25-34 (1996).
2. Bonfini, L., Migliaccio, E., Pelicci, G., Lanfrancone, L. &
Pelicci, P. G. Not all
Shc's roads lead to Ras.Trends Biochem. Sci. 21, 257-261 (1996)
3. Macleod, K. F. et al. p53-dependent and independent expression of
p21 during cell
growth, differentiation, and DNA damage. Genes Dev. 9, 935-944
(1995).