Silencing of human Int-6 impairs mitosis progression and inhibits cyclin B–Cdk1 activation

Morris, Christelle; Jalinot, Pierre

doi:10.1038/sj.onc.1208268

Cited by 29 publications

(36 citation statements)

References 40 publications

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“…MAD2L1, which was negatively regulated by eIF3e (Figures 3 and 4), is a component of the mitotic spindle attachment checkpoint; its dysfunction, through either reduced or increased expression, can cause aberrant chromosome segregation, and hence contribute to malignancy, in mammalian cells (Michel et al, 2001;Sotillo et al, 2007). Inhibition of eIF3e expression was shown previously to delay mitotic progression in human cells (Morris and Jalinot, 2005); our findings suggest that elevated MAD2L1 expression may contribute to this phenotype.…”

Section: Discussionsupporting

confidence: 54%

An oncogenic role of eIF3e/INT6 in human breast cancer

et al. 2010

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Altered expression of the eukaryotic translation initiation factor 3 (eIF3) subunit eIF3e/INT6 has been described in various types of human cancer, but the nature of its involvement in tumorigenesis is not yet clear. Using immunohistochemical analysis of 81 primary breast cancers, we found that high tumor grade correlated significantly with elevated cytoplasmic eIF3e level in epithelial tumor cells. Analysis of protein synthesis after siRNA-mediated knockdown in breast cancer cell lines indicated that eIF3e is not required for bulk translation. Microarray analysis of total and polysomal RNAs nonetheless identified distinct sets of mRNAs regulated either positively or negatively by eIF3e; functional classification of these revealed a marked enrichment of genes involved in cell proliferation, invasion and apoptosis. Validated mRNA targets regulated positively at the translational level by eIF3e included urokinase-type plasminogen activator and apoptotic regulator BCL-XL, whereas synthesis of proteins including the mitotic checkpoint component MAD2L1 was negatively regulated. Finally, eIF3e-depleted breast carcinoma cells showed reduced in vitro invasion and proliferation. Taken together, our study data suggest that eIF3e has a positive role in breast cancer progression. It regulates the translation, and in some cases abundance, of mRNAs involved in key aspects of cancer cell biology.

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Section: Discussionsupporting

confidence: 54%

An oncogenic role of eIF3e/INT6 in human breast cancer

et al. 2010

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“…In fission yeast, Yin6 enables proteasome activity by promoting the nuclear import of its Rpn5 subunit, and Yin6 inactivation causes defective cyclin B and securin degradation, leading to mitotic anomalies (Yen and Chang, 2000;Yen et al, 2003). In human cells, we showed that INT6 silencing also leads to mitosis alteration due to defects in spindle formation, chromosome segregation and cytokinesis (Morris and Jalinot, 2005).…”

Section: Introductionmentioning

confidence: 79%

“…We have reported previously that silencing of INT6 in HeLa cells does not modify duration of the G1 phase (Morris and Jalinot, 2005), thus providing an indication that the onset of DNA replication is not altered. To test possible defects during the replication process, we first measured the stability of MCM7 in control or INT6-depleted cells synchronized at the G1/S transition by a double thymidine block (Figure 5a).…”

Section: Int6 Regulates Mcm7 Stability S Buchsbaum Et Almentioning

confidence: 99%

Human INT6 interacts with MCM7 and regulates its stability during S phase of the cell cycle

Buchsbaum

Morris²,

Bochard³

et al. 2007

Oncogene

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The mouse int6 gene is a frequent integration site of the mouse mammary tumor virus and INT6 silencing by RNA interference in HeLa cells causes an increased number of cells in the G2/M phases of the cell cycle, along with mitotic defects. In this report, we investigated the functional significance of the interaction between INT6 and MCM7, which was observed in a two-hybrid screen performed with INT6 as bait. It was found that proteasome inhibition strengthens interaction between both proteins and that INT6 stabilizes MCM7. Removal of MCM7 from chromatin as replication proceeds was accelerated in INT6-silenced cells and reduced amounts of protein were transiently observed, followed by a correction resulting from stimulation of mcm7 gene expression. Synchronized cells depleted for either INT6 or MCM7 display a reduction in thymidine incorporation and a reinforced association of RPA and claspin with chromatin. These data show that INT6 stabilizes chromatin-bound MCM7 and that alteration of this effect is associated with replication deficiency.

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“…eIF3e is a cytoplasmic protein, but is also detected in the nucleus in many organisms including plants (Desbois et al, 1996;Watkins and Norbury, 2004;Yahalom et al, 2001). The role of nuclear eIF3e is still unclear, although it has been associated with (i) control of 26S proteasome activity (Yen et al, 2003), (ii) the COP9 signalosome (Yahalom et al, 2001), another regulator of proteolysis, (iii) human T-cell leukemia virus transcriptional transactivator (HTLV Tax) Tax activity, (iv) the 'nuclear speckle' proto-oncogene products Rfp and PML (Desbois et al, 1996;Morris-Desbois et al, 1999), and (v) spindle organization (Morris and Jalinot, 2005;Yen and Chang, 2000). Although eIF3e is not essential for global translation initiation in Schizosaccharomyces pombe (Bandyopadhyay et al, 2000;Zhou et al, 2005), there is good evidence that eIF3e plays a pivotal role in translation (Asano et al, 1997;Bandyopadhyay et al, 2002Bandyopadhyay et al, , 2000.…”

Section: Introductionmentioning

confidence: 99%

Arabidopsis eIF3e is regulated by the COP9 signalosome and has an impact on development and protein translation

et al. 2007

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SummaryThe roles of individual eukaryotic translation initiation factor 3 (eIF3) subunits are largely unclear, although some are essential, while others are thought to have regulatory roles. The 'e' subunit, also known as Int-6/Int6, is a candidate for a regulatory subunit as it is not essential for translation initiation in yeasts. eIF3e associates with the COP9 signalosome, and localizes to the nucleus in certain tissues. To further elucidate the roles of eIF3e, we have taken a genetic approach using Arabidopsis as a model system. Overexpression of eIF3e results in defects similar to mutations in the COP9 signalosome. eIF3e protein, but not transcript, over accumulates in csn mutants, and eIF3e is degraded in a proteasome-dependent fashion. In vitro and in vivo assays suggest that excess eIF3e inhibits translation. We conclude that the COP9 signalosome maintains a precise regulation of eIF3e levels, which is necessary for normal development in Arabidopsis.

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Silencing of human Int-6 impairs mitosis progression and inhibits cyclin B–Cdk1 activation

Cited by 29 publications

References 40 publications

An oncogenic role of eIF3e/INT6 in human breast cancer

An oncogenic role of eIF3e/INT6 in human breast cancer

Human INT6 interacts with MCM7 and regulates its stability during S phase of the cell cycle

Arabidopsis eIF3e is regulated by the COP9 signalosome and has an impact on development and protein translation

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