This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by MacLaren, A.
Right arrow Articles by Gillespie, D. A. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by MacLaren, A.
Right arrow Articles by Gillespie, D. A. F.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, October 2004, p. 9006-9018, Vol. 24, No. 20
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.20.9006-9018.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

c-Jun-Deficient Cells Undergo Premature Senescence as a Result of Spontaneous DNA Damage Accumulation

Ann MacLaren,1* Elizabeth J. Black,1 William Clark,1 and David A. F. Gillespie1,2

Beatson Institute for Cancer Research, Bearsden,1 Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, United Kingdom2

Received 28 January 2004/ Returned for modification 15 March 2004/ Accepted 23 June 2004

Mouse embryo fibroblasts deficient for the c-Jun proto-oncogene (c-Jun–/– MEF) undergo p53-dependent premature senescence in conventional culture. This phenotype becomes evident only after several cell divisions, suggesting that senescence may result from exposure to unknown environmental factors. Here, we show that c-Jun–/– MEF can proliferate successfully in low oxygen (3% O2), indicating that premature senescence under conventional culture conditions is a consequence of hyperoxic stress. c-Jun–/– MEF exhibit higher basal levels of DNA damage compared to normal fibroblasts in high but not low oxygen, implying that senescence results from chronic accumulation of spontaneous DNA damage. This accumulation may be attributable, at least in part, to inefficient repair, since DNA damage induced by {gamma} ionizing radiation and H2O2 persists for longer in c-Jun–/– MEF than in wild-type MEF. Unexpectedly, p53 expression, phosphorylation, and transcriptional activity are largely unaffected by oxygen exposure, indicating that the accumulation of spontaneous DNA damage does not result in chronic activation of p53 as judged by conventional criteria. Finally, we find that c-Jun associates with nuclear foci containing {gamma}H2AX and ATM following irradiation, suggesting a potential role for c-Jun in DNA repair processes per se.

* Corresponding author. Present address: The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-2825. Fax: (858) 784-2265. E-mail: annmac{at}scripps.edu.

Molecular and Cellular Biology, October 2004, p. 9006-9018, Vol. 24, No. 20
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.20.9006-9018.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Nakade, K., Pan, J., Yamasaki, T., Murata, T., Wasylyk, B., Yokoyama, K. K. (2009). JDP2 (Jun Dimerization Protein 2)-deficient Mouse Embryonic Fibroblasts Are Resistant to Replicative Senescence. J. Biol. Chem. 284: 10808-10817 [Abstract] [Full Text]  
  • Zhao, P., Xiao, X., Kim, A. S., Leite, M. F., Xu, J., Zhu, X., Ren, J., Li, J. (2008). c-Jun Inhibits Thapsigargin-Induced ER Stress Through Up-Regulation of DSCR1/Adapt78. Exp. Biol. Med. 233: 1289-1300 [Abstract] [Full Text]  
  • Wang, I-C., Chen, Y.-J., Hughes, D. E., Ackerson, T., Major, M. L., Kalinichenko, V. V., Costa, R. H., Raychaudhuri, P., Tyner, A. L., Lau, L. F. (2008). FoxM1 Regulates Transcription of JNK1 to Promote the G1/S Transition and Tumor Cell Invasiveness. J. Biol. Chem. 283: 20770-20778 [Abstract] [Full Text]  
  • Holmstrom, T. H., Mialon, A., Kallio, M., Nymalm, Y., Mannermaa, L., Holm, T., Johansson, H., Black, E., Gillespie, D., Salminen, T. A., Langel, U., Valdez, B. C., Westermarck, J. (2008). c-Jun Supports Ribosomal RNA Processing and Nucleolar Localization of RNA Helicase DDX21. J. Biol. Chem. 283: 7046-7053 [Abstract] [Full Text]  
  • Golding, S. E., Rosenberg, E., Neill, S., Dent, P., Povirk, L. F., Valerie, K. (2007). Extracellular Signal-Related Kinase Positively Regulates Ataxia Telangiectasia Mutated, Homologous Recombination Repair, and the DNA Damage Response. Cancer Res. 67: 1046-1053 [Abstract] [Full Text]  
  • Wang, Y.-H., Chiu, W.-T., Wang, Y.-K., Wu, C.-C., Chen, T.-L., Teng, C.-F., Chang, W.-T., Chang, H.-C., Tang, M.-J. (2007). Deregulation of AP-1 Proteins in Collagen Gel-induced Epithelial Cell Apoptosis Mediated by Low Substratum Rigidity. J. Biol. Chem. 282: 752-763 [Abstract] [Full Text]  
  • Yogev, O., Anzi, S., Inoue, K., Shaulian, E. (2006). Induction of Transcriptionally Active Jun Proteins Regulates Drug-induced Senescence. J. Biol. Chem. 281: 34475-34483 [Abstract] [Full Text]  
  • Chen, J., Goligorsky, M. S. (2006). Premature senescence of endothelial cells: Methusaleh's dilemma. Am. J. Physiol. Heart Circ. Physiol. 290: H1729-H1739 [Abstract] [Full Text]  
  • Laine, A., Ronai, Z. (2005). Ubiquitin Chains in the Ladder of MAPK Signaling. Sci Signal 2005: re5-re5 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»