|
Originally published In Press as doi:10.1074/jbc.M200933200 on March 7, 2002
J. Biol. Chem., Vol. 277, Issue 22, 19358-19366, May 31, 2002
Oncogenic H-Ras Enhances DNA Repair through the
Ras/Phosphatidylinositol 3-Kinase/Rac1 Pathway in NIH3T3 Cells
EVIDENCE FOR ASSOCIATION WITH REACTIVE OXYGEN SPECIES*
Hyun-Ju
Cho §,
Hye Gwang
Jeong§¶,
Jung-Sup
Lee§ ,
Eun-Rhan
Woo§¶,
Jin-Won
Hyun**,
Myung-Hee
Chung**, and
Ho
Jin
You §
From the Department of Pharmacology, School of
Medicine, the § Research Center for Proteineous
Materials, and the Departments of ¶ Pharmacy and Biological
Sciences, Chosun University, 375 Seosuk-dong, Kwangju 501-759, Korea
and the ** Department of Pharmacology, Seoul National
University College of Medicine, 28 Yongon-dong,
Seoul 110-799, Korea
This study investigated the role of oncogenic
H-Ras in DNA repair capacity in NIH3T3 cells. Expression of
dominant-positive H-Ras (V12-H-Ras) enhanced the host cell
reactivation of luciferase activity from UV-irradiated and
cisplatin-treated plasmids and also increased the unscheduled DNA
synthesis following cisplatin or UV treatment of cells. This observed
enhancement of DNA repair capacity was inhibited by transient
transfection with dominant-negative H-Ras (N17-H-Ras) or Rac1
(N17-Rac1) plasmids. Moreover, stable transfection of dominant-positive
Rac1 (V12-Rac1) further enhanced DNA repair capacity. Because reactive
oxygen species (ROS) are known to be a downstream effector of oncogenic
Ras, we examined the role of ROS in DNA repair capacity. We found that
ROS production by V12-H-Ras expression was mediated by the
Ras/phosphatidylinositol 3-kinase (PI3K)/Rac1/NADPH
oxidase-dependent pathway and that pretreatment of
V12-H-Ras-transformed cells with an antioxidant (N-acetylcysteine) and an NADPH oxidase inhibitor
(diphenyleneiodonium) decreased DNA repair capacity. Similarly,
treatment with PI3K inhibitors (wortmannin and LY294002) inhibited the
ability of oncogenic H-Ras to enhance DNA repair capacity. Furthermore,
inhibition of the Ras/PI3K/Rac1/NADPH oxidase pathway resulted in
increased sensitivity to cisplatin and UV in V12-H-Ras-expressing
NIH3T3 cells. Taken together, these results provide evidence that
oncogenic H-Ras activates DNA repair capacity through the
Ras/PI3K/Rac1/NADPH oxidase-dependent pathway and that
increased ROS production via this signaling pathway is required for
enhancement of the DNA repair capacity induced by oncogenic
H-Ras.
*
This work was supported by the Ministry of Science and
Technology of Korea and the Korea Science and Engineering
Foundation through the Research Center for Proteineous
Materials.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.:
82-62-230-6337; Fax: 82-62-233-3720; E-mail:
hjyou@mail.chosun.ac.kr.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

CiteULike Complore Connotea Del.icio.us Digg Reddit Technorati What's this?
This article has been cited by other articles:

|
 |

|
 |
 
M. B. Friis, K. G. Vorum, and I. H. Lambert
Volume-sensitive NADPH oxidase activity and taurine efflux in NIH3T3 mouse fibroblasts
Am J Physiol Cell Physiol,
June 1, 2008;
294(6):
C1552 - C1565.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
P. B. Kopnin, L. S. Agapova, B. P. Kopnin, and P. M. Chumakov
Repression of Sestrin Family Genes Contributes to Oncogenic Ras-Induced Reactive Oxygen Species Up-regulation and Genetic Instability
Cancer Res.,
May 15, 2007;
67(10):
4671 - 4678.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. B. Weidhaas, D. M. Eisenmann, J. M. Holub, and S. V. Nallur
A Conserved RAS/Mitogen-Activated Protein Kinase Pathway Regulates DNA Damage-Induced Cell Death Postirradiation in Radelegans
Cancer Res.,
November 1, 2006;
66(21):
10434 - 10438.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
Y. Zhao, L. Chaiswing, V. Bakthavatchalu, T. D. Oberley, and D. K. St. Clair
Ras mutation promotes p53 activation and apoptosis of skin keratinocytes
Carcinogenesis,
August 1, 2006;
27(8):
1692 - 1698.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
T. Ohta, M. Ohmichi, T. Hayasaka, S. Mabuchi, M. Saitoh, J. Kawagoe, K. Takahashi, H. Igarashi, B. Du, M. Doshida, et al.
Inhibition of Phosphatidylinositol 3-Kinase Increases Efficacy of Cisplatin in in Vivo Ovarian Cancer Models
Endocrinology,
April 1, 2006;
147(4):
1761 - 1769.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
I.-Y. Chang, C.-K. Youn, H.-B. Kim, M.-H. Kim, H.-J. Cho, Y. Yoon, Y.-S. Lee, M.-H. Chung, and H. J. You
Oncogenic H-Ras Up-regulates Expression of Ku80 to Protect Cells from {gamma}-Ray Irradiation in NIH3T3 Cells
Cancer Res.,
August 1, 2005;
65(15):
6811 - 6819.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
B. H. Jeon, G. Gupta, Y. C. Park, B. Qi, A. Haile, F. A. Khanday, Y.-X. Liu, J.-M. Kim, M. Ozaki, A. R. White, et al.
Apurinic/Apyrmidinic Endonuclease 1 Regulates Endothelial NO Production and Vascular Tone
Circ. Res.,
October 29, 2004;
95(9):
902 - 910.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
C.-K. Youn, M.-H. Kim, H.-J. Cho, H.-B. Kim, I.-Y. Chang, M.-H. Chung, and H. J. You
Oncogenic H-Ras Up-Regulates Expression of ERCC1 to Protect Cells from Platinum-Based Anticancer Agents
Cancer Res.,
July 15, 2004;
64(14):
4849 - 4857.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
K.-H. Shin, M. K. Kang, E. Dicterow, A. Kameta, M. A. Baluda, and N.-H. Park
Introduction of Human Telomerase Reverse Transcriptase to Normal Human Fibroblasts Enhances DNA Repair Capacity
Clin. Cancer Res.,
April 1, 2004;
10(7):
2551 - 2560.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M.-R. Lee, S.-H. Kim, H.-J. Cho, K.-Y. Lee, A. R. Moon, H. G. Jeong, J.-S. Lee, J.-W. Hyun, M.-H. Chung, and H. J. You
Transcription Factors NF-YA Regulate the Induction of Human OGG1 Following DNA-alkylating Agent Methylmethane Sulfonate (MMS) Treatment
J. Biol. Chem.,
March 12, 2004;
279(11):
9857 - 9866.
[Abstract]
[Full Text]
[PDF]
|
 |
|
Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.
|
Advertisement
Advertisement
|