Eukaryotic translation initiation factor 4E activity is modulated by HOXA9 at multiple levels.
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.
Topisirovic
Ivan
I
Institute for Research in Immunovirology and Cancer, University of Montreal, Montreal, Quebec H3T 1J4, Canada.
Kentsis
Alex
A
Perez
Jacqueline M
JM
Guzman
Monica L
ML
Jordan
Craig T
CT
Borden
Katherine L B
KL
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000208:Acute Disease; D000595:Amino Acid Sequence; D001854:Bone Marrow Cells / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors; D014158:Transcription, Genetic
D039561:Eukaryotic Initiation Factor-4E; C078492:HHEX protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors; C097899:homeobox protein HOXA9; D019938:Cyclin D1; D009955:Ornithine Decarboxylase