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 Topisirovic, I.
Right arrow Articles by Borden, K. L. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Topisirovic, I.
Right arrow Articles by Borden, K. L. B.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, February 2005, p. 1100-1112, Vol. 25, No. 3
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.3.1100-1112.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Eukaryotic Translation Initiation Factor 4E Activity Is Modulated by HOXA9 at Multiple Levels

Ivan Topisirovic,1,{dagger} Alex Kentsis,1 Jacqueline M. Perez,1 Monica L. Guzman,2 Craig T. Jordan,2 and Katherine L. B. Borden1*

Structural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York University, New York,1 Department of Medicine, University of Rochester, Rochester, New York2

Received 12 July 2004/ Returned for modification 19 August 2004/ Accepted 5 November 2004

The eukaryotic translation initiation factor 4E (eIF4E) alters gene expression on multiple levels. In the cytoplasm, eIF4E acts in the rate-limiting step of translation initiation. In the nucleus, eIF4E facilitates nuclear export of a subset of mRNAs. Both of these functions contribute to eIF4E's ability to oncogenically transform cells. We report here that the homeodomain protein, HOXA9, is a positive regulator of eIF4E. HOXA9 stimulates eIF4E-dependent export of cyclin D1 and ornithine decarboxylase (ODC) mRNAs in the nucleus, as well as increases the translation efficiency of ODC mRNA in the cytoplasm. These activities depend on direct interactions of HOXA9 with eIF4E and are independent of the role of HOXA9 in transcription. At the biochemical level, HOXA9 mediates these effects by competing with factors that repress eIF4E function, in particular the proline-rich homeodomain PRH/Hex. This competitive mechanism of eIF4E regulation is disrupted in a subset of leukemias, where HOXA9 displaces PRH from eIF4E, thereby contributing to eIF4E's dysregulation. In regard to these results and our previous finding that ~200 homeodomain proteins contain eIF4E binding sites, we propose that homeodomain modulation of eIF4E activity is a novel means through which this family of proteins implements their effects on growth and development.

* Corresponding author. Mailing address: Institute for Research in Immunovirology and Cancer, University of Montreal, Montreal, Quebec H3T 1J4, Canada. Phone: (514) 343-6291. Fax: (514) 343-7379. E-mail: katherine.borden{at}umontreal.ca.

{dagger} Present address: Institute for Research in Immunovirology and Cancer, University of Montreal, Montreal, Quebec, Canada.

Molecular and Cellular Biology, February 2005, p. 1100-1112, Vol. 25, No. 3
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.3.1100-1112.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Hu, Y.-L., Fong, S., Ferrell, C., Largman, C., Shen, W.-F. (2009). HOXA9 Modulates Its Oncogenic Partner Meis1 To Influence Normal Hematopoiesis. Mol. Cell. Biol. 29: 5181-5192 [Abstract] [Full Text]  
  • Assouline, S., Culjkovic, B., Cocolakis, E., Rousseau, C., Beslu, N., Amri, A., Caplan, S., Leber, B., Roy, D.-C., Miller, W. H. Jr, Borden, K. L. B. (2009). Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin. Blood 114: 257-260 [Abstract] [Full Text]  
  • Culjkovic, B., Tan, K., Orolicki, S., Amri, A., Meloche, S., Borden, K. L.B. (2008). The eIF4E RNA regulon promotes the Akt signaling pathway. JCB 181: 51-63 [Abstract] [Full Text]  
  • Hu, Y.-L., Passegue, E., Fong, S., Largman, C., Lawrence, H. J. (2007). Evidence that the Pim1 kinase gene is a direct target of HOXA9. Blood 109: 4732-4738 [Abstract] [Full Text]  
  • Nurtjahja-Tjendraputra, E., Fu, D., Phang, J. M., Richardson, D. R. (2007). Iron chelation regulates cyclin D1 expression via the proteasome: a link to iron deficiency-mediated growth suppression. Blood 109: 4045-4054 [Abstract] [Full Text]  
  • Laine, A., Topisirovic, I., Zhai, D., Reed, J. C., Borden, K. L. B., Ronai, Z. (2006). Regulation of p53 Localization and Activity by Ubc13. Mol. Cell. Biol. 26: 8901-8913 [Abstract] [Full Text]  
  • Culjkovic, B., Topisirovic, I., Skrabanek, L., Ruiz-Gutierrez, M., Borden, K. L.B. (2006). eIF4E is a central node of an RNA regulon that governs cellular proliferation. JCB 175: 415-426 [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»