Impairment of Cytoplasmic eIF6 Activity Restricts Lymphomagenesis and Tumor Progression without Affecting Normal Growth

Abstract

Eukaryotic Initiation Factor 6 (eIF6) controls translation by regulating 80S subunit formation. eIF6 is overexpressed in tumors. Here, we demonstrate that eIF6 inactivation delays tumorigenesis and reduces tumor growth in vivo. eIF6(+/-) mice resist to Myc-induced lymphomagenesis and have prolonged tumor-free survival and reduced tumor growth. eIF6(+/-) mice are also protected by p53 loss. Myc-driven lymphomas contain PKCβII and phosphorylated eIF6; eIF6 is phosphorylated by tumor-derived PKCβII, but not by the eIF4F activator mTORC1. Mutation of PKCβII phosphosite of eIF6 reduces tumor growth. Thus, eIF6 is a rate-limiting controller of initiation of translation, able to affect tumorigenesis and tumor growth. Modulation of eIF6 activity, independent from eIF4F complex, may lead to a therapeutical avenue in tumor therapy.

Translational control by 80S formation and 60S availability: The central role of eIF6, a rate limiting factor in cell cycle progression and tumorigenesis

“…Mutation of eIF6 in the PKC consensus phosphosite Ser235 reduces the rate of transformation, suggesting a role of this residue in tumorigenesis. 38 These data are in agreement with the overexpression of eIF6 in carcinomas 39,40 and establish a link between the known promoting role of PKCβ in lymphomagenesis (for example, see review in ref. 41) and the phosphorylation of eIF6.…”

Eukaryotic initiation factor 6 modulates myofibroblast differentiation at transforming growth factor-β1 transcription level via H2A.Z occupancy and Sp1 recruitment

“…These data indicate that a more differentiated and functional cell cycle takes part in the fibrogenic phenotype of eIF6 +/− fibroblasts. In partial keeping with this observation, eIF6 down-regulation in pre-B-cells reduced the S-phase fraction and increased the G0/G1 fraction, thereby impairing mitotic cycle progression (Miluzio et al, 2011). In accordance with our results, the high eIF6 expression observed in dysplastic carcinomas suggests that eIF6 is involved in the transition to malignancy by impairing the cell's differentiated capacity (Rosso et al, 2004).…”

“…The injection of eIF6 mRNA into one blastomere of two-cell-stage embryos resulted in a bent phenotype and fewer apoptotic cells during Xenopus laevis development, because eIF6 seemed to regulate the translation of specific mRNAs as an anti-apoptotic factor (De Marco et al, 2010). Moreover, eIF6 overexpression has been reported to cause an aberrant eye development in X. laevis (Miluzio et al, 2011). Furthermore, eIF6 overexpression has been found in selected cancer types, such as colorectal carcinomas (Sanvito et al, 2000), head and neck cancer (Rosso et al, 2004), and malignant mesothelioma (Biffo et al, 1997).…”

“…Furthermore, eIF6 overexpression has been found in selected cancer types, such as colorectal carcinomas (Sanvito et al, 2000), head and neck cancer (Rosso et al, 2004), and malignant mesothelioma (Biffo et al, 1997). It has been proposed that eIF6 is a rate-limiting controller of the initiation of translation, able to affect tumorigenesis and tumor growth (Gandin et al, 2008) and that the impairment of eIF6 activity in cytoplasm restricts lymphomagenesis and tumor progression (Miluzio et al, 2011). In addition, the physiological significance of eIF6 also impacts on inherited Shwachman Diamond syndrome (SDS).…”

Translation factors and ribosomal proteins control tumor onset and progression: how?

“…First, Myc acts as a general inducer of protein synthesis, as it increases transcription of rDNA in the nucleolus by directing the assembly of the Pol I preinitiation complex or by enhancing the expression of rDNA transcription factors such as UBF. 117,118 Second, genetic strategies that reduce translation to normal levels in Myc transgenic mice by either downregulation of eIF6 101 or rpL24, 40 reveal that the oncogenic potential of Myc fully relies on the translational machinery. In addition, deregulation of mitotic translational control as a consequence of Myc hyperactivation leads to genome instability by modulating the translation of specific mRNAs.…”