Ras mediates translation initiation factor 4E-induced malignant transformation.
Translation initiation factor eIF-4E binds to the eukaryotic mRNA 5' cap structure (m7 GpppN, where N is any nucleotide). eIF-4E is a limiting factor in translation and plays a key role in regulation of translation. We have shown previously that overexpression of eIF-4E in rodent fibroblasts results in tumorigenic transformation. eIF-4E also exhibits mitogenic activity when microinjected into serum-starved NIH-3T3 cells. To understand the mechanisms by which eIF-4E exerts its mitogenic property, we examined the involvement of the Ras signaling pathway in this activity. Here, we report that Ras is activated in eIF-4E-overexpressing cells, as the proportion of GTP-bound Ras is increased. Overexpression of the negative effector of cellular Ras, GTPase activating protein, causes reversion of the transformed phenotype. Furthermore, we show that neutralizing antibodies to Ras, or a dominant-negative mutant of Ras, inhibit the mitogenic activity of eIF-4E. We conclude that eIF-4E exerts its mitogenic and oncogenic activities by the activation of Ras.
Lazaris-Karatzas
A
A
Department of Biochemistry, McGill University, Montréal, Québec, Canada.
Smith
M R
MR
Frederickson
R M
RM
Jaramillo
M L
ML
Liu
Y L
YL
Kung
H F
HF
Sonenberg
N
N
D016475:3T3 Cells; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D015197:Carcinogenicity Tests; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D039561:Eukaryotic Initiation Factor-4E; D020690:GTPase-Activating Proteins; D051379:Mice; D009154:Mutation / Q000235:genetics; D010448:Peptide Initiation Factors / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000502:physiology*; D011506:Proteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D020703:ras GTPase-Activating Proteins
D039561:Eukaryotic Initiation Factor-4E; D020690:GTPase-Activating Proteins; D010448:Peptide Initiation Factors; D011506:Proteins; D020703:ras GTPase-Activating Proteins; D016283:Proto-Oncogene Proteins p21(ras)