Malignant transformation by the eukaryotic translation initiation factor 3 subunit p48 (eIF3e)

Mayeur, Greg L.; Hershey, John W.B.

doi:10.1016/s0014-5793(02)02307-4

Cited by 74 publications

(55 citation statements)

References 36 publications

(46 reference statements)

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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: 78%

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: 78%

An oncogenic role of eIF3e/INT6 in human breast cancer

et al. 2010

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“…HC11, MCF10A, and NIH3T3 cells stably transfected with a vector expressing 3e5 formed colonies in soft agar, and subcutaneous injection of transformed MCF10A and HC11 cells into nude or BALB/c mice, respectively, formed nodular growths (9). In another study, NIH3T3 cells expressing 3e5 formed foci, grew in soft agar, and were more resistant to serum starvation-induced apoptosis (10). However, these models had limitations for our study of possible 3e5-induced changes in protein synthesis.…”

Section: Development Of An Nih3t3 Cell Line Containing a Singlementioning

confidence: 94%

“…Integration at Int6 (7) occurs in the gene for eIF3e (8) at any of several introns and leads to the synthesis of truncated mRNAs (5). Expression the eIF3e protein resulting from truncation of the mRNA at intron 5 (3e5; amino acid residues 1-157) is sufficient to cause malignant transformation of both mammary and non-mammary cell lines (9,10) and the formation of mammary tumors in transgenic mice (11), suggesting that expression of 3e5 per se, rather than the loss of one of the Eif3e alleles, is responsible for tumorigenesis.…”

mentioning

confidence: 99%

Expression of Truncated Eukaryotic Initiation Factor 3e (eIF3e) Resulting from Integration of Mouse Mammary Tumor Virus (MMTV) Causes a Shift from Cap-dependent to Cap-independent Translation

Chiluiza

Bargo

Callahan

et al. 2011

Journal of Biological Chemistry

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Integration of mouse mammary tumor virus (MMTV) at the common integration site Int6 occurs in the gene encoding eIF3e, the p48 subunit of translation initiation factor eIF3. Integration is at any of several introns of the Eif3e gene and causes the expression of truncated Eif3e mRNAs. Ectopic expression of the truncated eIF3e protein resulting from integration at intron 5 (3e5) induces malignant transformation, but by an unknown mechanism. Because eIF3e makes up at least part of the binding site for eIF4G, we examined the effects of 3e5 expression on protein synthesis. We developed an NIH3T3 cell line that contains a single copy of the 3e5 sequence at a predetermined genomic site. Co-immunoprecipitation indicated diminished binding of eIF3 to eIF4G, signifying a reduction in recruitment of the mRNA-unwinding machinery to the 43 S preinitiation complex. Cell growth and overall protein synthesis were decreased. Translation driven by the eIF4G-independent hepatitis C virus internal ribosome entry sequence (HCV IRES) in a bicistronic mRNA was increased relative to cap-dependent translation. Endogenous mRNAs encoding XIAP, c-Myc, CYR61, and Pim-1, which are translated in a cap-independent manner, were shifted to heavier polysomes whereas mRNAs encoding GAPDH, actin, L32, and L34, which are translated in a cap-dependent manner, were shifted to lighter polysomes. We propose that expression of 3e5 diminishes eIF4G interaction with eIF3 and causes abnormal gene expression at the translational level. The correlation between up-regulation of cap-independent translation and MMTV-induced tumorigenesis contrasts with the well established model for malignant transformation involving up-regulation of highly cap-dependent translation.

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“…1A) that has been reported to be generated by MMTV integration. Overexpression of this truncated protein transforms cells in culture, and the injection of these cells into nude mice induces tumor formation (47,48).…”

Section: Identification Of Int6 (Eif3e/p48) As An Hif-2␣-specificmentioning

confidence: 99%

“…1A) that is dominant negative. The overexpression of these truncated proteins can transform cells in culture, and injection of these transformed cells into nude mice can induce tumor formation (47,48). Furthermore, human Int6 may also indirectly influence proteolysis via at least three proteins that have been identified as Int6-binding proteins, Tax (49), Ret finger protein (50), and p56 (51).…”

mentioning

confidence: 99%

Mammalian Tumor Suppressor Int6 Specifically Targets Hypoxia Inducible Factor 2α for Degradation by Hypoxia- and pVHL-independent Regulation

Chen¹,

Uchida²,

Endler³

et al. 2007

Journal of Biological Chemistry

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The hypoxia-inducible factors HIF-1␣ and HIF-2␣ are structurally similar as regards their DNA-binding and dimerization domains, but differ in their transactivation domains and, as is shown by experiments using hif-1␣؊/؊ and hif-2␣ ؊/؊ mice, in their functions. This implies that HIF-1␣ and HIF-2␣ may have unique target genes. To address this discrepancy and identify HIF-2␣-specific target genes, we performed yeast two-hybrid analysis and identified the tumor suppressor Int6/eIF3e/p48 as a novel target gene product involved in HIF-2␣ regulation. The int6 gene was first identified from a screen in which the mouse mammary tumor virus was employed as an insertional mutagen to identify genes whose functions are critical for breast tumor formation. Here, by using two-hybrid analysis, immunoprecipitation in mammalian cells, and HRE-reporter assays, we report the specific interaction of HIF-2␣ (but not HIF-1␣ or HIF-3␣) with Int6. The results indicate that the direct interaction of Int6 induces proteasome inhibitor-sensitive HIF-2␣ degradation. This degradation was clearly observed in renal cell carcinoma 786-O cells, and was found to be both hypoxia-and pVHL-independent. Furthermore, Int6 protein knockdown by int6-siRNA vectors or the dominant-negative mutant Int6-⌬C increased endogenous HIF-2␣ expression, even under normoxia, and induced sets of critical angiogenic factors comprising vascular endoplasmic growth factor, angiopoietin, and basic fibroblast growth factor mRNA. These results indicate that Int6 is a novel and critical determinant of HIF-2␣-dependent angiogenesis as well as cancer formation, and that int6-siRNA transfer may be an effective therapeutic strategy in pathological conditions such as heart and brain ischemia, hepatic cirrhosis, and obstructive vessel diseases.Hypoxia-responsive genes are involved in glucose transport, glycolysis, erythropoiesis, angiogenesis, vasodilation, and respiratory rate. However, they are also involved in the pathogenesis of many cardiovascular diseases and cancer (1, 2). Central to many molecular and physiological responses to hypoxia in most mammals cells are the hypoxia-inducible factors HIF-1␣ and HIF-2␣ (HIFs), 2 heterodimers with HIF-1␤ (also referred to as aryl hydrocarbon receptor nuclear translocator, ARNT) (3-5). Both HIF-1␣ and ARNT belong to the basic helix loop helix Per-Arnt-Sim (PAS) family of transcription factors, which share several conserved structural domains (6).Under normoxia, HIF-1␣ is ubiquitinated via interaction with the von Hippel-Lindau tumor suppressor protein (pVHL) and is subsequently degraded by the 26 S proteasome (7-12). pVHL, the recognition component of an E3 ubiquitin ligase complex, binds HIF-1␣ when it is hydroxylated at proline residues 402 and 577 (13-15). The proline hydroxylation of HIF-1␣ is catalyzed by prolyl hydroxylase domain-containing proteins, which are members of the 2-oxoglutarate-dependent dioxygenase superfamily whose activity requires O 2 as a cofactor (16,17). During hypoxia, the activity of prolyl hydroxylase domainco...

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Malignant transformation by the eukaryotic translation initiation factor 3 subunit p48 (eIF3e)

Cited by 74 publications

References 36 publications

An oncogenic role of eIF3e/INT6 in human breast cancer

An oncogenic role of eIF3e/INT6 in human breast cancer

Expression of Truncated Eukaryotic Initiation Factor 3e (eIF3e) Resulting from Integration of Mouse Mammary Tumor Virus (MMTV) Causes a Shift from Cap-dependent to Cap-independent Translation

Mammalian Tumor Suppressor Int6 Specifically Targets Hypoxia Inducible Factor 2α for Degradation by Hypoxia- and pVHL-independent Regulation

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