scholarly journals Translational control of programmed cell death: eukaryotic translation initiation factor 4E blocks apoptosis in growth-factor-restricted fibroblasts with physiologically expressed or deregulated Myc.

1996 ◽  
Vol 16 (11) ◽  
pp. 6573-6581 ◽  
Author(s):  
V A Polunovsky ◽  
I B Rosenwald ◽  
A T Tan ◽  
J White ◽  
L Chiang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Translation Initiation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Individual Growth ◽  
Eukaryotic Translation Initiation Factor ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation ◽  
Survival Signaling

There is increasing evidence that cell cycle transit is potentially lethal, with survival depending on the activation of metabolic pathways which block apoptosis. However, the identities of those pathways coupling cell cycle transit to survival remain undefined. Here we show that the eukaryotic translation initiation factor 4E (eIF4E) can mediate both proliferative and survival signaling. Overexpression of eIF4E completely substituted for serum or individual growth factors in preserving the viability of established NIH 3T3 fibroblasts. An eIF4E mutant (Ser-53 changed to Ala) defective in mediating its growth-factor-regulated functions was also defective in its survival signaling. Survival signaling by enforced expression of eIF4E did not result from autocrine release of survival factors, nor did it lead to increased expression of the apoptosis antagonists Bcl-2 and Bcl-XL. In addition, the execution apparatus of the apoptotic response in eIF4E-overexpressing cells was found to be intact. Increased expression of eIF4E was sufficient to inhibit apoptosis in serum-restricted primary fibroblasts with enforced expression of Myc. In contrast, activation of Ha-Ras, which is required for eIF4E proliferative signaling, did not suppress Myc-induced apoptosis. These data suggest that the eIF4E-activated pathways leading to survival and cell cycle progression are distinct. This dual signaling of proliferation and survival might be the basis for the potency of eIF4E as an inducer of neoplastic transformation.

scholarly journals Cancer-Associated Eukaryotic Translation Initiation Factor 1A Mutants Impair Rps3 and Rps10 Binding and Enhance Scanning of Cell Cycle Genes

2018 ◽  
Vol 39 (3) ◽  
Author(s):  
Urmila Sehrawat ◽  
Femke Koning ◽  
Shaked Ashkenazi ◽  
Gil Stelzer ◽  
Dena Leshkowitz ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Translation Initiation ◽  
Ribosome Profiling ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation Initiation Factor ◽  
Eukaryotic Translation ◽  
Cell Cycle Genes ◽  
Eukaryotic Translation Initiation

ABSTRACTProtein synthesis is linked to cell proliferation, and its deregulation contributes to cancer. Eukaryotic translation initiation factor 1A (eIF1A) plays a key role in scanning and AUG selection and differentially affects the translation of distinct mRNAs. Its unstructured N-terminal tail (NTT) is frequently mutated in several malignancies. Here we report that eIF1A is essential for cell proliferation and cell cycle progression. Ribosome profiling of eIF1A knockdown cells revealed a substantial enrichment of cell cycle mRNAs among the downregulated genes, which are predominantly characterized by a lengthy 5′ untranslated region (UTR). Conversely, eIF1A depletion caused a broad stimulation of 5′ UTR initiation at a near cognate AUG, unveiling a prominent role of eIF1A in suppressing 5′ UTR translation. In addition, the AUG context-dependent autoregulation of eIF1 was disrupted by eIF1A depletion, suggesting their cooperation in AUG context discrimination and scanning. Importantly, cancer-associated eIF1A NTT mutants augmented the eIF1A positive effect on a long 5′ UTR, while they hardly affected AUG selection. Mechanistically, these mutations diminished the eIF1A interaction with Rps3 and Rps10 implicated in scanning arrest. Our findings suggest that the reduced binding of eIF1A NTT mutants to the ribosome retains its open state and facilitates scanning of long 5′ UTR-containing cell cycle genes.

scholarly journals Transcript Levels of the Eukaryotic Translation Initiation Factor 5A Gene Peak at Early G1 Phase of the Cell Cycle in the Dinoflagellate Crypthecodinium cohnii

2002 ◽  
Vol 68 (5) ◽  
pp. 2278-2284 ◽  
Author(s):  
K. L. Chan ◽  
D. New ◽  
S. Ghandhi ◽  
F. Wong ◽  
C. M. C. Lam ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Amino Acid ◽  
Translation Initiation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation Initiation Factor ◽  
Crypthecodinium Cohnii ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

ABSTRACT A cDNA encoding a eukaryotic translation initiation factor 5A (eIF-5A) homolog in heterotrophic dinoflagellate Crypthecodinium cohnii (CceIF-5A) was isolated through random sequencing of a cDNA library. The predicted amino acid sequence possesses the 12 strictly conserved amino acids around lysine 52 (equivalent to lysine 50 or 51 in other eukaryotes). A single 1.2-kb band was detected in Northern blot analysis. In synchronized C. cohnii cells, the transcript level peaked at early G1 and decreased dramatically on the entry to S phase. Although this has not been previously reported, studies of budding yeast (Saccharomyces cerevisiae) and certain mammalian cell types suggest a role for eIF-5A in the G1/S transition of the eukaryotic cell cycle. Phylogenetic trees constructed with 26 other published eIF-5A sequences suggest that CceIF-5A, while falling within the eukaryotic branches, forms a lineage separate from those of the plants, animals, and archaebacteria. The posttranslational modification of eIF-5A by a transfer of a 4-aminobutyl moiety from spermidine to conserved lysine 50 or 51, forming amino acid hypusine, is the only demonstrated specific function of polyamines in cell proliferation. It has been suggested that polyamines stimulate population growth of bloom-forming dinoflagellates in the sea. We demonstrate here putrescine-stimulated cell proliferation. Furthermore, ornithine decarboxylase inhibitor d-difluoromethylornithine and the specific hypusination inhibitor N-guanyl-1,7-diaminoheptane exhibited inhibitory effects in two species of dinoflagellates. The possible links of polyamines and saxitoxin synthesis to the arginine cycle are also discussed.

scholarly journals Discovery and characterization of conserved binding of eIF4E 1 (CBE1), a eukaryotic translation initiation factor 4E–binding plant protein

2018 ◽  
Vol 293 (44) ◽  
pp. 17240-17247 ◽  
Author(s):  
Ryan M. Patrick ◽  
Jessica C. H. Lee ◽  
Jade R. J. Teetsel ◽  
Soo-Hyun Yang ◽  
Grace S. Choy ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Translation Initiation ◽  
Translation Initiation Factor ◽  
Plant Protein ◽  
Initiation Factor ◽  
Binding Motif ◽  
Specific Cell ◽  
Eukaryotic Translation Initiation Factor ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

In many eukaryotes, translation initiation is regulated by proteins that bind to the mRNA cap–binding protein eukaryotic translation initiation factor 4E (eIF4E). These proteins commonly prevent association of eIF4E with eIF4G or form repressive messenger ribonucleoproteins that exclude the translation machinery. Such gene-regulatory mechanisms in plants, and even the presence of eIF4E-interacting proteins other than eIF4G (and the plant-specific isoform eIFiso4G, which binds eIFiso4E), are unknown. Here, we report the discovery of a plant-specific protein, conserved binding of eIF4E 1 (CBE1). We found that CBE1 has an evolutionarily conserved eIF4E-binding motif in its N-terminal domain and binds eIF4E or eIFiso4E in vitro. CBE1 thereby forms cap-binding complexes and is an eIF4E-dependent constituent of these complexes in vivo. Of note, plant mutants lacking CBE1 exhibited dysregulation of cell cycle–related transcripts and accumulated higher levels of mRNAs encoding proteins involved in mitosis than did WT plants. Our findings indicate that CBE1 is a plant protein that can form mRNA cap–binding complexes having the potential for regulating gene expression. Because mammalian translation factors are known regulators of cell cycle progression, we propose that CBE1 may represent such first translation factor–associated plant-specific cell cycle regulator.

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