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

Institute for Research in Immunovirology and Cancer, University of Montreal, Montreal, Quebec H3T 1J4, Canada.
Molecular and Cellular Biology (Impact Factor: 5.04). 03/2005; 25(3):1100-12. DOI: 10.1128/MCB.25.3.1100-1112.2005
Source: PubMed

ABSTRACT 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 approximately 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.

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    • "Along the same line, Hox nuclear partners identified by highthroughput approaches are not obligatory transcription factors. These observations are in accordance with other individual studies describing a molecular link between Hox proteins and nuclear export (Topisirovic et al., 2005), DNA replication (Luo et al., 2004; Salsi et al., 2009; Miotto and Graba, 2010) or histone modification (Shen et al., 2001; Agelopoulos et al., 2012). "
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    • "The eIF4E-Emx2 association was further proved to happen in axons of olfactory neurons where it was hypothesized to provide mRNA translation control. Regarding Hox proteins, Topisirovic et al. (2005) identified that HOXA9 can modulate translation both at the level of mRNA export and translation efficiency. This takes place by a direct interaction with eIF4E and most significantly , contrary to bcd, PRH, or Prep1, consists in a stimulation of eIF4E activity, both in the nucleus and cytoplasm (Fig. 1F). "
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    • "The Drosophila homeoprotein Bicoid represses translation of caudal mRNA by directly binding to the 3' untranslated region of caudal mRNA (Dubnau & Struhl, 1996). HOXA9 has been reported to bind the translation initiation factor eIF4E and to stimulate eIF4E-dependent export of cyclin D1 mRNA (Topisirovic et al., 2005). HOXB7 binds Ku proteins and stimulates DNA repair (Rubin et al., 2007). "
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