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: 4.78). 03/2005; 25(3):1100-12. DOI: 10.1128/MCB.25.3.1100-1112.2005
Source: PubMed


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.

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Available from: Ivan Topisirovic
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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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    ABSTRACT: Background: Hox proteins are key developmental regulators involved in almost every embryonic tissue for specifying cell fates along longitudinal axes or during organ formation. It is thought that the panoply of Hox activities relies on interactions with tissue-, stage-, and/or cell-specific transcription factors. High-throughput approaches in yeast or cell culture systems have shown that Hox proteins bind to various types of nuclear and cytoplasmic components, illustrating their remarkable potential to influence many different cell regulatory processes. However, these approaches failed to identify a relevant number of context-specific transcriptional partners, suggesting that these interactions are hard to uncover in non-physiological conditions. Here we discuss this problematic. Results: In this review, we present intrinsic Hox molecular signatures that are probably involved in multiple (yet specific) interactions with transcriptional partners. We also recapitulate the current knowledge on Hox cofactors, highlighting the difficulty to tracking context-specific cofactors through traditional large-scale approaches. Conclusion: We propose experimental approaches that will allow a better characterisation of interaction networks underlying Hox contextual activities in the next future.
    Full-text · Article · Jan 2014 · Developmental Dynamics
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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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    ABSTRACT: Hox proteins are conserved homeodomain transcription factors involved in the control of embryo patterning, organ development and cell differentiation during animal development and adult life. Although recognizably active in gene regulation, accumulating reports support that Hox proteins are also active in controlling other molecular processes like mRNA translation, DNA repair, initiation of DNA replication and possibly modulation of signal transduction. Here we review experimental evidence as well as databases entries indicative of non-transcriptional activities of Hox proteins. Developmental Dynamics, 2013. © 2013 Wiley Periodicals, Inc.
    Preview · Article · Jan 2014 · Developmental Dynamics
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    • "First, Hox proteins have been associated with translational functions. HOXA9 and HOXA13, for example, interact with the initiation factor of translation, eIF4E [22,23]. Interaction between HOXA9 and eIF4E stimulates mRNA transport by eIF4E and translation efficiency [22]. "
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    ABSTRACT: Hox proteins are conserved homeodomain transcription factors known to be crucial regulators of animal development. As transcription factors, the functions and modes of action (co-factors, target genes) of Hox proteins have been very well studied in a multitude of animal models. However, a handful of reports established that Hox proteins may display molecular activities distinct from gene transcription regulation. Here, we reveal that Hoxa2 interacts with 20S proteasome subunits and RCHY1 (also known as PIRH2), an E3 ubiquitin ligase that targets p53 for degradation. We further show that Hoxa2 promotes proteasome-dependent degradation of RCHY1 in an ubiquitin-independent manner. Correlatively, Hoxa2 alters the RCHY1-mediated ubiquitination of p53 and promotes p53 stabilization. Together, our data establish that Hoxa2 can regulate the proteasomal degradation of RCHY1 and stabilization of p53.
    Full-text · Article · Nov 2013 · PLoS ONE
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