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 Chen, P.-L.
Right arrow Articles by Lee, W.-H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chen, P.-L.
Right arrow Articles by Lee, W.-H.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, May 2005, p. 3535-3542, Vol. 25, No. 9
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.9.3535-3542.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Inactivation of CtIP Leads to Early Embryonic Lethality Mediated by G1 Restraint and to Tumorigenesis by Haploid Insufficiency

Phang-Lang Chen,1,{dagger} Feng Liu,1,{dagger} Suna Cai,1 Xiaoqin Lin,1 Aihua Li,1 Yumay Chen,2 Bingnan Gu,1 Eva Y.-H. P. Lee,1 and Wen-Hwa Lee1*

Department of Biological Chemistry, College of Medicine, University of California, Irvine, Irvine, California 92697,1 Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 782452

Received 16 November 2004/ Returned for modification 25 December 2004/ Accepted 3 February 2005

CtIP interacts with a group of tumor suppressor proteins including RB (retinoblastoma protein), BRCA1, Ikaros, and CtBP, which regulate cell cycle progression through transcriptional repression as well as chromatin remodeling. However, how CtIP exerts its biological function in cell cycle progression remains elusive. To address this issue, we generated an inactivated Ctip allele in mice by inserting a neo gene into exon 5. The corresponding Ctip–/– embryos died at embryonic day 4.0 (E4.0), and the blastocysts failed to enter S phase but accumulated in G1, leading to a slightly elevated cell death. Mouse NIH 3T3 cells depleted of Ctip were arrested at G1 with the concomitant increase in hypophosphorylated Rb and Cdk inhibitors, p21. However, depletion of Ctip failed to arrest Rb–/– mouse embryonic fibroblasts (MEF) or human osteosarcoma Saos-2 cells at G1, suggesting that this arrest is RB dependent. Importantly, the life span of Ctip+/– heterozygotes was shortened by the development of multiple types of tumors, predominantly, large lymphomas. The wild-type Ctip allele and protein remained detectable in these tumors, suggesting that haploid insufficiency of Ctip leads to tumorigenesis. Taken together, this finding uncovers a novel G1/S regulation in that CtIP counteracts Rb-mediated G1 restraint. Deregulation of this function leads to a defect in early embryogenesis and contributes, in part, to tumor formation.

* Corresponding author. Mailing address: University of California, Irvine, Sprague Hall, Room 124, Irvine, CA 92697. Phone: (949) 824-4492. Fax: (949) 824-9767. E-mail: whlee{at}uci.edu.

{dagger} The first two authors contributed equally to this work.

Molecular and Cellular Biology, May 2005, p. 3535-3542, Vol. 25, No. 9
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.9.3535-3542.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lee, S., Sakakibara, S., Maruo, S., Zhao, B., Calderwood, M. A., Holthaus, A. M., Lai, C.-Y., Takada, K., Kieff, E., Johannsen, E. (2009). Epstein-Barr Virus Nuclear Protein 3C Domains Necessary for Lymphoblastoid Cell Growth: Interaction with RBP-J{kappa} Regulates TCL1. J. Virol. 83: 12368-12377 [Abstract] [Full Text]  
  • Huertas, P., Jackson, S. P. (2009). Human CtIP Mediates Cell Cycle Control of DNA End Resection and Double Strand Break Repair. J. Biol. Chem. 284: 9558-9565 [Abstract] [Full Text]  
  • Wu, M., Soler, D. R., Abba, M. C., Nunez, M. I., Baer, R., Hatzis, C., Llombart-Cussac, A., Llombart-Bosch, A., Aldaz, C. M. (2007). CtIP Silencing as a Novel Mechanism of Tamoxifen Resistance in Breast Cancer. Mol Cancer Res 5: 1285-1295 [Abstract] [Full Text]  
  • Luo, S., Mao, C., Lee, B., Lee, A. S. (2006). GRP78/BiP Is Required for Cell Proliferation and Protecting the Inner Cell Mass from Apoptosis during Early Mouse Embryonic Development. Mol. Cell. Biol. 26: 5688-5697 [Abstract] [Full Text]  
  • Liu, F., Lee, W.-H. (2006). CtIP Activates Its Own and Cyclin D1 Promoters via the E2F/RB Pathway during G1/S Progression. Mol. Cell. Biol. 26: 3124-3134 [Abstract] [Full Text]  
  • Oswald, F., Winkler, M., Cao, Y., Astrahantseff, K., Bourteele, S., Knochel, W., Borggrefe, T. (2005). RBP-J{kappa}/SHARP Recruits CtIP/CtBP Corepressors To Silence Notch Target Genes. Mol. Cell. Biol. 25: 10379-10390 [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»