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J Biol Chem, Vol. 274, Issue 12, 7936-7940, March 19, 1999
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From the Human diploid fibroblasts eventually lose the
capacity to replicate in culture and enter a viable but
nonproliferative state of senescence. Recently, it has been
demonstrated that retroviral-mediated gene transfer into primary
fibroblasts of an activated ras gene (V12ras)
rapidly accelerates development of the senescent phenotype. Using this
in vitro system, we have sought to define the mediators of
Ras-induced senescence. We demonstrate that expression of V12Ras results in an increase in intracellular and in particular,
mitochondrial reactive oxygen species. The ability of V12Ras to induce
growth arrest and senescence is shown to be partially inhibited by
coexpression of an activated rac1 gene. A more dramatic
rescue of V12Ras-expressing cells is demonstrated when the cells are
placed in a low oxygen environment, a condition in which reactive
oxygen species production is inhibited. In addition, in a 1% oxygen
environment, Ras is unable to trigger an increase in the level of the
cyclin-dependent kinase inhibitor p21 or to activate the
senescent program. Under normoxic (20% O2) conditions, the
V12Ras senescent phenotype is demonstrated to be unaffected by
scavengers of superoxide but rescued by scavengers of hydrogen
peroxide. These results suggest that in normal diploid cells, Ras
proteins regulate oxidant production and that a rise in intracellular
H2O2 represents a critical signal mediating
replicative senescence.
Cardiology Branch and the ¶ Pathology
Section, Laboratory of Molecular Growth
Regulation,
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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