Expression of truncated Int6/eIF3e in mammary alveolar epithelium leads to persistent hyperplasia and tumorigenesis

Mack, David L.; Boulanger, Corinne A.; Callahan, Robert; Smith, Gilbert H.

doi:10.1186/bcr1742

Cited by 25 publications

(28 citation statements)

References 30 publications

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“…eIF3e in breast cancer M Grzmil et al encoding eIF3e as a site of MMTV integration (Marchetti et al, 1995), the biological role of eIF3e in tumorigenesis has proved difficult to determine. The expression of truncated EIF3E mRNA in mammary epithelial cells induced a transformed phenotype (Mayeur and Hershey, 2002) and in a mouse model truncated eIF3e expression led to persistent hyperplasia and tumorigenesis in mammary alveolar epithelium (Mack et al, 2007). These findings could be consistent either with a gain of function for the truncated alleles, or with a dominant negative effect.…”

Section: Discussionmentioning

confidence: 77%

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: Discussionmentioning

confidence: 77%

An oncogenic role of eIF3e/INT6 in human breast cancer

et al. 2010

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“…These correlations suggest that elevated expression of eIF3m is an attribute of tumor tissues and/or proliferating cancer cell lines. It was reported that eIF3e in its truncated form leads to persistent hyperplasia and tumorigenesis in mammary alveolar epithelium (Mack et al, 2007) and subunits of eIF3 also showed oncogencity when modified by truncation or phosphorylation. However, in this study we could not detect any variant of eIF3m mRNA that could be considered as truncated.…”

Section: Discussionmentioning

confidence: 99%

“…Elevated expression of eIF3i in breast cancer was suggested to facilitate mTOR-dependent growth transformation (Ahlemann et al, 2006). eIF3e, also called INT6 and originally known as a tumor suppressor (Green et al, 2007) and shown to be expressed in a truncated form in tumors, was intensively investigated (Mack et al, 2007) and has been implicated in tumor progression (Morris et al, 2007). eIF3f was reported to be lost in melanoma and pancreatic cancer (Doldan et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

eIF3m expression influences the regulation of tumorigenesis-related genes in human colon cancer

Hong

et al. 2010

Oncogene

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Abnormal regulation of gene expression is essential for tumorigenesis. Recent studies indicate that regulation of oncogene expression and neoplastic transformation are controlled by subunits of eukaryotic translation initiation factors (eIFs). Here we focused on eIF3 performing a pivotal role in protein synthesis and the differential expression of its subunits in cancer. The most uncharacterized non-core subunit eIF3m was confirmed to be highly expressed in human cancer cell lines and colon cancer patient tissues. By expression silencing with eIF3m-specific small interfering RNA (siRNA), we confirmed that eIF3m influences cell proliferation, cell cycle progression and cell death in human colon cancer cell line HCT-116. Using a ribonomics approach, we identified a subset of elF3m-influenced genes and showed that the expression of two highly represented tumorigenesis-related genes, MIF and MT2, were affected by eIF3m at the mRNA level. We also confirmed eIF3m-dependent regulation of MT2A downstream molecule CDC25A, which is necessary for cell cycle progression in HCT-116 cells. These results suggest that eIF3m mediates regulation of tumorigenesis-related genes in human colon cancer. Further investigations on tumorigenesis-related genes and their regulation by eIFs will provide clues for designing targeted therapy for cancer.

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“…They also might bring some interesting new ideas on the mechanisms allowing coupling of DNA replication and histone synthesis. Finally, this activity by influencing genomic stability is certainly important to consider for gaining a better understanding of the oncogenic and genomic instability effects resulting from INT6 alteration (Marchetti et al 1995;Yen and Chang 2000;Rasmussen et al 2001;Morris and Jalinot 2005;Mack et al 2007). …”

Section: Relationship Between Histone Mrna Translation and Other Rolementioning

confidence: 99%

INT6 interacts with MIF4GD/SLIP1 and is necessary for efficient histone mRNA translation

Neusiedler¹,

Mocquet²,

Limousin³

et al. 2012

RNA

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The INT6/EIF3E protein has been implicated in mouse and human breast carcinogenesis. This subunit of the eIF3 translation initiation factor that includes a PCI domain exhibits specific features such as presence in the nucleus and ability to interact with other important cellular protein complexes like the 26S proteasome and the COP9 signalosome. It has been previously shown that INT6 was not essential for bulk translation, and this protein is considered to regulate expression of specific mRNAs. Based on the results of a two-hybrid screen performed with INT6 as bait, we characterize in this article the MIF4GD/SLIP1 protein as an interactor of this eIF3 subunit. MIF4GD was previously shown to associate with SLBP, which binds the stem-loop located at the 39 end of the histone mRNAs, and to be necessary for efficient translation of these cell cycle-regulated mRNAs that lack a poly(A) tail. In line with the interaction of both proteins, we show using the RNA interference approach that INT6 is also essential to S-phase histone mRNA translation. This was observed by analyzing expression of endogenous histones and by testing heterologous constructs placing the luciferase reporter gene under the control of the stem-loop element of various histone genes. With such a reporter plasmid, silencing and overexpression of INT6 exerted opposite effects. In agreement with these results, INT6 and MIF4GD were observed to colocalize in cytoplasmic foci. We conclude from these data that INT6, by establishing interactions with MIF4GD and SLBP, plays an important role in translation of poly(A) minus histone mRNAs.

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Expression of truncated Int6/eIF3e in mammary alveolar epithelium leads to persistent hyperplasia and tumorigenesis

Cited by 25 publications

References 30 publications

An oncogenic role of eIF3e/INT6 in human breast cancer

An oncogenic role of eIF3e/INT6 in human breast cancer

eIF3m expression influences the regulation of tumorigenesis-related genes in human colon cancer

INT6 interacts with MIF4GD/SLIP1 and is necessary for efficient histone mRNA translation

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