scholarly journals eIF4E promotes nuclear export of cyclin D1 mRNAs via an element in the 3′UTR

2005 ◽  
Vol 169 (2) ◽  
pp. 245-256 ◽  
Author(s):  
Biljana Culjkovic ◽  
Ivan Topisirovic ◽  
Lucy Skrabanek ◽  
Melisa Ruiz-Gutierrez ◽  
Katherine L.B. Borden
Keyword(s):  
Cyclin D1 ◽  
Nuclear Export ◽  
Cellular Proliferation ◽  
Nuclear Bodies ◽  
Translation Initiation Factor ◽  
Cellular Growth ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Functional Sites ◽  
Eukaryotic Translation Initiation

The eukaryotic translation initiation factor eIF4E is a critical modulator of cellular growth with functions in the nucleus and cytoplasm. In the cytoplasm, recognition of the 5′ m7G cap moiety on all mRNAs is sufficient for their functional interaction with eIF4E. In contrast, we have shown that in the nucleus eIF4E associates and promotes the nuclear export of cyclin D1, but not GAPDH or actin mRNAs. We determined that the basis of this discriminatory interaction is an ∼100-nt sequence in the 3′ untranslated region (UTR) of cyclin D1 mRNA, we refer to as an eIF4E sensitivity element (4E-SE). We found that cyclin D1 mRNA is enriched at eIF4E nuclear bodies, suggesting these are functional sites for organization of specific ribonucleoproteins. The 4E-SE is required for eIF4E to efficiently transform cells, thereby linking recognition of this element to eIF4E mediated oncogenic transformation. Our studies demonstrate previously uncharacterized fundamental differences in eIF4E-mRNA recognition between the nuclear and cytoplasmic compartments and further a novel level of regulation of cellular proliferation.

scholarly journals eIF4E is a central node of an RNA regulon that governs cellular proliferation

2006 ◽  
Vol 175 (3) ◽  
pp. 415-426 ◽  
Author(s):  
Biljana Culjkovic ◽  
Ivan Topisirovic ◽  
Lucy Skrabanek ◽  
Melisa Ruiz-Gutierrez ◽  
Katherine L.B. Borden
Keyword(s):  
Cell Cycle ◽  
Messenger Rna ◽  
Cell Cycle Progression ◽  
Cellular Proliferation ◽  
Mrna Export ◽  
Nuclear Bodies ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

This study demonstrates that the eukaryotic translation initiation factor eIF4E is a critical node in an RNA regulon that impacts nearly every stage of cell cycle progression. Specifically, eIF4E coordinately promotes the messenger RNA (mRNA) export of several genes involved in the cell cycle. A common feature of these mRNAs is a structurally conserved, ∼50-nucleotide element in the 3′ untranslated region denoted as an eIF4E sensitivity element. This element is sufficient for localization of capped mRNAs to eIF4E nuclear bodies, formation of eIF4E-specific ribonucleoproteins in the nucleus, and eIF4E-dependent mRNA export. The roles of eIF4E in translation and mRNA export are distinct, as they rely on different mRNA elements. Furthermore, eIF4E-dependent mRNA export is independent of ongoing RNA or protein synthesis. Unlike the NXF1-mediated export of bulk mRNAs, eIF4E-dependent mRNA export is CRM1 dependent. Finally, the growth-suppressive promyelocytic leukemia protein (PML) inhibits this RNA regulon. These data provide novel perspectives into the proliferative and oncogenic properties of eIF4E.

scholarly journals Stability of Eukaryotic Translation Initiation Factor 4E mRNA Is Regulated by HuR, and This Activity Is Dysregulated in Cancer

2008 ◽  
Vol 29 (5) ◽  
pp. 1152-1162 ◽  
Author(s):  
Ivan Topisirovic ◽  
Nadeem Siddiqui ◽  
Slobodanka Orolicki ◽  
Lucy A. Skrabanek ◽  
Mathieu Tremblay ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Cellular Proliferation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Malignant Cells ◽  
Functional Connection ◽  
Eukaryotic Translation Initiation Factor ◽  
Eukaryotic Translation ◽  
Transcript Stability ◽  
Eukaryotic Translation Initiation

ABSTRACT Eukaryotic translation initiation factor 4E (eIF4E) is encoded by a potent oncogene which is highly elevated in many human cancers. Few studies have investigated how the level, and thus activity, of eIF4E is regulated in healthy (noncancerous) cells and how they become elevated in malignant cells. Here, our studies reveal a novel mechanism by which eIF4E levels are regulated at the level of mRNA stability. Two factors known to modulate transcript stability, HuR and the p42 isoform of AUF1, compete for binding to the 3′ untranslated regions (3′UTRs) of eIF4E mRNAs. We identified a distinct AU-rich element in the 3′UTR of eIF4E which is responsible for HuR-mediated binding and stabilization. Our studies show that HuR is upregulated in malignant cancer specimens characterized by high eIF4E levels and that its depletion leads to reduction in eIF4E levels. Further, HuR and eIF4E regulate a common set of transcripts involved in cellular proliferation (cyclin D1 and c-myc) and neoangiogenesis (vascular endothelial growth factor), which suggests a functional connection between HuR and eIF4E in the regulation of these important processes. In summary, we present a novel model for the regulation of eIF4E expression and show that this model is relevant to elevation of eIF4E levels in malignant cells.

scholarly journals Defects in tRNA Processing and Nuclear Export InduceGCN4 Translation Independently of Phosphorylation of the α Subunit of Eukaryotic Translation Initiation Factor 2

2000 ◽  
Vol 20 (7) ◽  
pp. 2505-2516 ◽  
Author(s):  
Hongfang Qiu ◽  
Cuihua Hu ◽  
James Anderson ◽  
Glenn R. Björk ◽  
Srimonti Sarkar ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Nuclear Export ◽  
Rnase P ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Initiator Trna ◽  
Eukaryotic Translation ◽  
Initiation Factor 2 ◽  
Eukaryotic Translation Initiation ◽  
Translation Initiation Factor 2

ABSTRACT Induction of GCN4 translation in amino acid-starved cells involves the inhibition of initiator tRNAMetbinding to eukaryotic translation initiation factor 2 (eIF2) in response to eIF2 phosphorylation by protein kinase GCN2. It was shown previously that GCN4 translation could be induced independently of GCN2 by overexpressing a mutant tRNAAAC Val (tRNAVal*) or the RNA component of RNase MRP encoded by NME1. Here we show that overexpression of the tRNA pseudouridine 55 synthase encoded byPUS4 also leads to translational derepression ofGCN4 (Gcd− phenotype) independently of eIF2 phosphorylation. Surprisingly, the Gcd− phenotype of high-copy-number PUS4 (hcPUS4) did not require PUS4 enzymatic activity, and several lines of evidence indicate thatPUS4 overexpression did not diminish functional initiator tRNAMet levels. The presence of hcPUS4 or hcNME1 led to the accumulation of certain tRNA precursors, and their Gcd− phenotypes were reversed by overexpressing the RNA component of RNase P (RPR1), responsible for 5′-end processing of all tRNAs. Consistently, overexpression of a mutant pre-tRNATyr that cannot be processed by RNase P had a Gcd− phenotype. Interestingly, the Gcd− phenotype of hcPUS4also was reversed by overexpressing LOS1, required for efficient nuclear export of tRNA, and los1Δ cells have a Gcd− phenotype. Overproduced PUS4 appears to impede 5′-end processing or export of certain tRNAs in the nucleus in a manner remedied by increased expression of RNase P or LOS1, respectively. The mutant tRNAVal* showed nuclear accumulation in otherwise wild-type cells, suggesting a defect in export to the cytoplasm. We propose that yeast contains a nuclear surveillance system that perceives defects in processing or export of tRNA and evokes a reduction in translation initiation at the step of initiator tRNAMet binding to the ribosome.

scholarly journals Aberrant Eukaryotic Translation Initiation Factor 4E-Dependent mRNA Transport Impedes Hematopoietic Differentiation and Contributes to Leukemogenesis

2003 ◽  
Vol 23 (24) ◽  
pp. 8992-9002 ◽  
Author(s):  
Ivan Topisirovic ◽  
Monica L. Guzman ◽  
Melanie J. McConnell ◽  
Jonathan D. Licht ◽  
Biljana Culjkovic ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Translation Initiation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Transport Function ◽  
Mrna Transport ◽  
Eukaryotic Translation Initiation Factor ◽  
Nuclear Function ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

ABSTRACT The eukaryotic translation initiation factor 4E (eIF4E) acts as both a key translation factor and as a promoter of nucleocytoplasmic transport of specific transcripts. Traditionally, its transformation capacity in vivo is attributed to its role in translation initiation in the cytoplasm. Here, we demonstrate that elevated eIF4E impedes granulocytic and monocytic differentiation. Our subsequent mutagenesis studies indicate that this block is a result of dysregulated eIF4E-dependent mRNA transport. These studies indicate that the RNA transport function of eIF4E could contribute to leukemogenesis. We extended our studies to provide the first evidence that the nuclear transport function of eIF4E contributes to human malignancy, specifically in a subset of acute and chronic myelogenous leukemia patients. We observe an increase in eIF4E-dependent cyclin D1 mRNA transport and a concomitant increase in cyclin D1 protein levels. The aberrant nuclear function of eIF4E is due to abnormally large eIF4E bodies and the loss of regulation by the proline-rich homeodomain PRH. We developed a novel tool to modulate this transport activity. The introduction of IκB, the repressor of NF-κB, leads to suppression of eIF4E, elevation of PRH, reorganization of eIF4E nuclear bodies, and subsequent downregulation of eIF4E-dependent mRNA transport. Thus, our findings indicate that this nuclear function of eIF4E can contribute to leukemogenesis by promoting growth and by impeding differentiation.

scholarly journals Reciprocal interplay of miR-497 and MALAT1 promotes tumourigenesis of adrenocortical cancer

2019 ◽  
Vol 26 (7) ◽  
pp. 677-688 ◽  
Author(s):  
Nunki Hassan ◽  
Jing Ting Zhao ◽  
Anthony Glover ◽  
Bruce G Robinson ◽  
Stan B Sidhu
Keyword(s):  
Cellular Proliferation ◽  
Chromosomal Region ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Adrenocortical Cancer ◽  
Recurrence Rates ◽  
Eukaryotic Translation ◽  
Functional Roles ◽  
Cycle Arrest ◽  
Eukaryotic Translation Initiation

Adrenocortical carcinoma (ACC) has high recurrence rates and poor prognosis with limited response to conventional cancer therapy. Recent contributions of high-throughput transcriptomic profiling identified microRNA-497 (miR-497) as significantly underexpressed, while lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) as overexpressed in ACC. miR-497 is located in the chromosomal region 17p13.1, in which there is a high frequency of loss of heterozygosity in ACC. We aim to investigate the interaction of miR-497 and MALAT1 in ACC and its functional roles in the process of tumourigenesis. In this study, we demonstrated miR-497 post-transcriptionally repressed MALAT1 while MALAT1 also competes for miR-497 binding to its molecular target, EIF4E (eukaryotic translation initiation factor 4E). We showed that overexpression of miR-497 and silencing of MALAT1 suppressed cellular proliferation and induced cell cycle arrest through downregulation of EIF4E expression. Furthermore, MALAT1 directly binds to SFPQ (splicing factor proline and glutamine rich) protein, indicating its multifaceted roles in ACC pathophysiology. This is the first study to identify the feedback axis of miR-497-MALAT1/EIF4E in ACC tumourigenesis, providing novel insights into the molecular functions of noncoding RNAs in ACC.

scholarly journals Eukaryotic Translation Initiation Factor 4E Activity Is Modulated by HOXA9 at Multiple Levels

2005 ◽  
Vol 25 (3) ◽  
pp. 1100-1112 ◽  
Author(s):  
Ivan Topisirovic ◽  
Alex Kentsis ◽  
Jacqueline M. Perez ◽  
Monica L. Guzman ◽  
Craig T. Jordan ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Nuclear Export ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Homeodomain Protein ◽  
Translation Efficiency ◽  
Eukaryotic Translation Initiation Factor ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation ◽  
Multiple Levels

ABSTRACT The eukaryotic translation initiation factor 4E (eIF4E) alters gene expression on multiple levels. In the cytoplasm, eIF4E acts in the rate-limiting step of translation initiation. In the nucleus, eIF4E facilitates nuclear export of a subset of mRNAs. Both of these functions contribute to eIF4E's ability to oncogenically transform cells. We report here that the homeodomain protein, HOXA9, is a positive regulator of eIF4E. HOXA9 stimulates eIF4E-dependent export of cyclin D1 and ornithine decarboxylase (ODC) mRNAs in the nucleus, as well as increases the translation efficiency of ODC mRNA in the cytoplasm. These activities depend on direct interactions of HOXA9 with eIF4E and are independent of the role of HOXA9 in transcription. At the biochemical level, HOXA9 mediates these effects by competing with factors that repress eIF4E function, in particular the proline-rich homeodomain PRH/Hex. This competitive mechanism of eIF4E regulation is disrupted in a subset of leukemias, where HOXA9 displaces PRH from eIF4E, thereby contributing to eIF4E's dysregulation. In regard to these results and our previous finding that ∼200 homeodomain proteins contain eIF4E binding sites, we propose that homeodomain modulation of eIF4E activity is a novel means through which this family of proteins implements their effects on growth and development.

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