X-Message-Number: 11944
Date: Fri, 11 Jun 1999 08:51:02 -0700 (PDT)
From: Doug Skrecky <>
Subject: ras proteins induce senescence

Authors
  Lee AC.  Fenster BE.  Ito H.  Takeda K.  Bae NS.  Hirai T.  Yu ZX.  Ferrans
  VJ.  Howard BH.  Finkel T.
Institution
  Cardiology Branch, National Institutes of Health, Bethesda, Maryland 20892,
  USA.
Title
  Ras proteins induce
  senescence by altering the intracellular levels of reactive oxygen species.
Source
  Journal of Biological Chemistry.  274(12):7936-40, 1999 Mar 19.
Abstract
  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.

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