Reduction of translation initiation factor 4E decreases the malignancy of ras ‐transformed cloned rat embryo fibroblasts

Abstract

Expression of the T24ras oncogene induces malignancy (tumor growth, invasion and metastasis) in cloned rat embryo fibroblasts (CREF T24). In CREF T24, the rate of phosphorylation of eukaryotic translation initiation factor 4E (elF-4E) is increased, resulting in increased protein synthesis rates. We have recently shown that reducing the protein levels of elF-4E in CREF T24 (AME line) markedly decreases soft-agar colonization, increases tumor latency periods and increases tumor doubling times without significantly altering monolayer growth. In this study, cells with reduced elF-4E had delayed and reduced invasiveness and decreased experimental metastasis. Furthermore, reduced elF-4E levels correlated with decreased expression of the metastasis-associated 92-kDa collagenase type-IV and exon-6 variants of the CD44 adhesion molecule [CD44(6v)]. Reduced elF-4E levels correlated inversely with increased levels of the putative metastasis-suppressor protein nm23. Cell lines established from AWE tumors and lung metastases exhibited increased levels of elF-4E protein and protein synthesis rates compared to the AWE line. Tumor-derived AS4E had the shortened tumor latency periods of CREF T24 but displayed the slow tumor-growth rates of AWE.Tumor-derived AS4E exhibited the metastatic capacity of CREF T24 controls. Furthermore, tumor-and lung-nodule-derived AS4E expressed levels of CD44 (6v) and the 92-kDa collagenase type IV comparable to CREF 124 and displayed reduced levels of nm23 relative to AWE. These results demonstrate that elF-4E is an important effector molecule involved in oncogenic p2 I '%nduced malignant transformation.

Milk-borne lactocrine-acting factors affect gene expression patterns in the developing neonatal porcine uterus

“…Translational control of gene expression can be particularly important during development and differentiation of eukaryotic cells and tissues (Sonenberg & Hinnebusch 2009). As is the case for other transcripts, translation of both VEGFA (De Benedetti & Graff 2004, Zhou et al 2006 and MMP9 (Graff et al 1995, De Benedetti & Graff 2004) involves eukaryotic initiation factor eIF-4E, a critical component of cap-dependent translation (Sonenberg & Hinnebusch 2009). Expression of both of these lactocrine-sensitive factors may be regulated translationally to a significant degree.…”

The eukaryotic initiation factor 4E-binding proteins and apoptosis

“…[26][27][28][29][30][31] This may involve effects of eIF4E on the translation of a variety of mRNAs, especially ones that, due to the existence of extensive secondary structure in their 5 0 -UTRs, have a high requirement for eIF4F (and in particular its eIF4A helicase activity; for recent reviews see Mamane et al 32 and Clemens 33 ). The possible links between eIF4E and cell transformation are underlined by the numerous observations that cancer cells often display high levels of eIF4E, especially tumors that are classed as aggressively metastatic.…”

The antiviral drug ribavirin does not mimic the 7-methylguanosine moiety of the mRNA cap structure in vitro

“…Overexpression of eIF4E in cultured mammalian cells produces rapid growth (De Benedetti and Rhoads 1990), causes them to form tumors in nude mice (Lazaris-Karatzas et al 1990), and prevents apoptosis after growth factor restriction (Polunovsky et al 1996). Conversely, reduction of eIF4E expression decreases protein synthesis, cell growth rate, and malignant transformation (De Benedetti et al 1991;Rinker-Schaeffer et al 1993), including invasiveness, metastasis, and angiogenesis in mice (Graff et al 1995;Nathan et al 1997). A wide variety of naturally occurring cancers is associated with overexpression of eIF4E (De Benedetti and Graff 2004).…”