Repression of Sestrin Family Genes Contributes to Oncogenic Ras-Induced ROS Up-Regulation and Genetic Instability
Oncogenic mutations within RAS genes and inactivation of p53 are the most common events in cancer. Earlier we reported that activated Ras contributes to chromosome instability, especially in p53-deficient cells. Here we show that an increase in intracellular reactive oxygen species (ROS) and oxidati...
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Published in | Cancer research (Chicago, Ill.) Vol. 67; no. 10; pp. 4671 - 4678 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
15.05.2007
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Abstract | Oncogenic mutations within
RAS
genes and inactivation of p53 are the most common events in cancer. Earlier we reported that activated Ras contributes to chromosome instability, especially in p53-deficient cells. Here we show that an increase in intracellular reactive oxygen species (ROS) and oxidative DNA damage represents a major mechanism of Ras-induced mutagenesis. Introduction of oncogenic H- or N-Ras caused elevated intracellular ROS, accumulation of 8-oxo-dG and increased number of chromosome breaks in mitotic cells, which were prevented by antioxidant N-acethyl-L-cysteine (NAC). By using Ras mutants that selectively activate either of the three major targets of Ras (Raf, RalGDS and PI3K) as well as dominant-negative Rac1 and RalA mutants and inhibitors of MEK1 and p38 MAPKs we have demonstrated that several Ras effectors independently mediate ROS up-regulation. Introduction of oncogenic
RAS
resulted in repression of transcription from sestrin family genes
SESN1
and
SESN3
, which encode antioxidant modulators of peroxiredoxins. Inhibition of mRNAs from these genes in control cells by RNAi increased substantially ROS levels and mutagenesis. Ectopic expression of
SESN1
and
SESN3
from lentiviral constructs interfered with Ras-induced ROS increase suggesting their important contribution to the effect. The stability of Ras-induced increase in ROS was dependent on a p53 function: in the p53-positive cells displaying activation of p53 in response to Ras only transient (4–7 days) elevation of ROS was observed whereas in the p53-deficient cells the up-regulation was permanent. The reversion to normal ROS levels in the Ras-expressing p53-positive cells correlated with up-regulation of p53-responsive genes, including reactivation of
SESN1
gene. Thus, changes in expression of sestrins can represent important determinant of genetic instability in neoplastic cells showing simultaneous dysfunctions of Ras and p53. |
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AbstractList | Oncogenic mutations within
RAS
genes and inactivation of p53 are the most common events in cancer. Earlier we reported that activated Ras contributes to chromosome instability, especially in p53-deficient cells. Here we show that an increase in intracellular reactive oxygen species (ROS) and oxidative DNA damage represents a major mechanism of Ras-induced mutagenesis. Introduction of oncogenic H- or N-Ras caused elevated intracellular ROS, accumulation of 8-oxo-dG and increased number of chromosome breaks in mitotic cells, which were prevented by antioxidant N-acethyl-L-cysteine (NAC). By using Ras mutants that selectively activate either of the three major targets of Ras (Raf, RalGDS and PI3K) as well as dominant-negative Rac1 and RalA mutants and inhibitors of MEK1 and p38 MAPKs we have demonstrated that several Ras effectors independently mediate ROS up-regulation. Introduction of oncogenic
RAS
resulted in repression of transcription from sestrin family genes
SESN1
and
SESN3
, which encode antioxidant modulators of peroxiredoxins. Inhibition of mRNAs from these genes in control cells by RNAi increased substantially ROS levels and mutagenesis. Ectopic expression of
SESN1
and
SESN3
from lentiviral constructs interfered with Ras-induced ROS increase suggesting their important contribution to the effect. The stability of Ras-induced increase in ROS was dependent on a p53 function: in the p53-positive cells displaying activation of p53 in response to Ras only transient (4–7 days) elevation of ROS was observed whereas in the p53-deficient cells the up-regulation was permanent. The reversion to normal ROS levels in the Ras-expressing p53-positive cells correlated with up-regulation of p53-responsive genes, including reactivation of
SESN1
gene. Thus, changes in expression of sestrins can represent important determinant of genetic instability in neoplastic cells showing simultaneous dysfunctions of Ras and p53. |
Author | Kopnin, Pavel B. Kopnin, Boris P. Agapova, Larissa S. Chumakov, Peter M. |
AuthorAffiliation | 1 Engelhardt Institute of Molecular Biology, 119991 Moscow, Russia 2 University of Oslo, Centre for Medical Studies in Russia, 119334 Moscow, Russia 3 Institute of Carcinogenesis, Russian Blokhin Cancer Research Center, Moscow, Russia 4 Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, USA |
AuthorAffiliation_xml | – name: 2 University of Oslo, Centre for Medical Studies in Russia, 119334 Moscow, Russia – name: 4 Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, USA – name: 3 Institute of Carcinogenesis, Russian Blokhin Cancer Research Center, Moscow, Russia – name: 1 Engelhardt Institute of Molecular Biology, 119991 Moscow, Russia |
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Snippet | Oncogenic mutations within
RAS
genes and inactivation of p53 are the most common events in cancer. Earlier we reported that activated Ras contributes to... |
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Title | Repression of Sestrin Family Genes Contributes to Oncogenic Ras-Induced ROS Up-Regulation and Genetic Instability |
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