scholarly journals Proteins of the Nucleolus of Dictyostelium discoideum: Nucleolar Compartmentalization, Targeting Sequences, Protein Translocations and Binding Partners

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 167 ◽  
Author(s):  
Danton O’Day
Keyword(s):  
Cell Cycle ◽  
Dictyostelium Discoideum ◽  
Cell Cycle Checkpoint ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Tumour Necrosis Factor Receptor ◽  
Cancer Type ◽  
Binding Partners ◽  
Nucleolar Proteins ◽  
C Terminus

The nucleoli of Dictyostelium discoideum have a comparatively unique, non-canonical, localization adjacent to the inner nuclear membrane. The verified nucleolar proteins of this eukaryotic microbe are detailed while other potential proteins are introduced. Heat shock protein 32 (Hsp32), eukaryotic translation initiation factor 6 (eIF6), and tumour necrosis factor receptor-associated protein 1 (TRAP1) are essential for cell survival. NumA1, a breast cancer type 1 susceptibility protein-C Terminus domain-containing protein linked to cell cycle, functions in the regulation of nuclear number. The cell cycle checkpoint kinase 2 homologue forkhead-associated kinase A (FhkA) and BRG1-associated factor 60a homologue Snf12 are also discussed. While nucleoli appear homogeneous ultrastructurally, evidence for nucleolar subcompartments exists. Nucleolar localization sequences (NoLS) have been defined that target proteins to either the general nucleolar area or to a specific intranucleolar domain. Protein translocations during mitosis are protein-specific and support the multiple functions of the Dictyostelium nucleolus. To enrich the picture, binding partners of NumA1, the most well-characterized nucleolar protein, are examined: nucleolar Ca2+-binding protein 4a (CBP4a), nuclear puromycin-sensitive aminopeptidase A (PsaA) and Snf12. The role of Dictyostelium as a model for understanding the contribution of nucleolar proteins to various diseases and cellular stress is discussed throughout the review.

scholarly journals CLN3 expression is sufficient to restore G1-to-S-phase progression in Saccharomyces cerevisiae mutants defective in translation initiation factor eIF4E

1999 ◽  
Vol 340 (1) ◽  
pp. 135-141 ◽  
Author(s):  
Parisa DANAIE ◽  
Michael ALTMANN ◽  
Michael N. HALL ◽  
Hans TRACHSEL ◽  
Stephen B. HELLIWELL
Keyword(s):  
Cell Cycle ◽  
S Phase ◽  
Translation Initiation Factor ◽  
Yeast Cells ◽  
Initiation Factor ◽  
G1 Phase ◽  
Mrna Levels ◽  
Wild Type ◽  
Phase Progression ◽  
Type Gene

The essential cap-binding protein (eIF4E) of Saccharomycescerevisiae is encoded by the CDC33 (wild-type) gene, originally isolated as a mutant, cdc33-1, which arrests growth in the G1 phase of the cell cycle at 37 °C. We show that other cdc33 mutants also arrest in G1. One of the first events required for G1-to-S-phase progression is the increased expression of cyclin 3. Constructs carrying the 5ʹ-untranslated region of CLN3 fused to lacZ exhibit weak reporter activity, which is significantly decreased in a cdc33-1 mutant, implying that CLN3 mRNA is an inefficiently translated mRNA that is sensitive to perturbations in the translation machinery. A cdc33-1 strain expressing either stable Cln3p (Cln3-1p) or a hybrid UBI4 5ʹ-CLN3 mRNA, whose translation displays decreased dependence on eIF4E, arrested randomly in the cell cycle. In these cells CLN2 mRNA levels remained high, indicating that Cln3p activity is maintained. Induction of a hybrid UBI4 5ʹ-CLN3 message in a cdc33-1 mutant previously arrested in G1 also caused entry into a new cell cycle. We conclude that eIF4E activity in the G1-phase is critical in allowing sufficient Cln3p activity to enable yeast cells to enter a new cell cycle.

scholarly journals Zinc is required for structural stability of the C-terminus of archaeal translation initiation factor aIF2β

FEBS Letters ◽  
2002 ◽  
Vol 517 (1-3) ◽  
pp. 155-158 ◽  
Author(s):  
Pablo Gutiérrez ◽  
Stéphane Coillet-Matillon ◽  
Cheryl Arrowsmith ◽  
Kalle Gehring
Keyword(s):  
Structural Stability ◽  
Translation Initiation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
C Terminus

scholarly journals uS3/Rps3 controls fidelity of translation termination and programmed stop codon readthrough in co-operation with eIF3

2019 ◽  
Vol 47 (21) ◽  
pp. 11326-11343 ◽  
Author(s):  
Kristýna Poncová ◽  
Susan Wagner ◽  
Myrte Esmeralda Jansen ◽  
Petra Beznosková ◽  
Stanislava Gunišová ◽  
...  
Keyword(s):  
Translational Control ◽  
Stop Codon ◽  
Translation Termination ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
C Terminus ◽  
Context Specific ◽  
Stop Codon Readthrough

Abstract Ribosome was long considered as a critical yet passive player in protein synthesis. Only recently the role of its basic components, ribosomal RNAs and proteins, in translational control has begun to emerge. Here we examined function of the small ribosomal protein uS3/Rps3, earlier shown to interact with eukaryotic translation initiation factor eIF3, in termination. We identified two residues in consecutive helices occurring in the mRNA entry pore, whose mutations to the opposite charge either reduced (K108E) or increased (R116D) stop codon readthrough. Whereas the latter increased overall levels of eIF3-containing terminating ribosomes in heavy polysomes in vivo indicating slower termination rates, the former specifically reduced eIF3 amounts in termination complexes. Combining these two mutations with the readthrough-reducing mutations at the extreme C-terminus of the a/Tif32 subunit of eIF3 either suppressed (R116D) or exacerbated (K108E) the readthrough phenotypes, and partially corrected or exacerbated the defects in the composition of termination complexes. In addition, we found that K108 affects efficiency of termination in the termination context-specific manner by promoting incorporation of readthrough-inducing tRNAs. Together with the multiple binding sites that we identified between these two proteins, we suggest that Rps3 and eIF3 closely co-operate to control translation termination and stop codon readthrough.

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 Up-regulation of ANKDR49, a poor prognostic factor, regulates cell proliferation of gliomas

2017 ◽  
Vol 37 (4) ◽  
Author(s):  
Chunyan Hao ◽  
Hubin Duan ◽  
Hao Li ◽  
Mingyang Pei ◽  
Yueting Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Malignant Glioma ◽  
Glioma Cells ◽  
Translation Initiation Factor ◽  
The Cancer Genome Atlas ◽  
Initiation Factor ◽  
Poor Prognostic Factor ◽  
Malignant Glioma Cells ◽  
U87 Cells

The Ankyrin repeat domain 49 (ANKRD49) is an evolutionarily conserved protein, which is related to mediate protein–protein interaction. However, the function of ANKRD49 in human glioma remains elusive. Mining through The Cancer Genome Atlas (TCGA) database, we found that the expression of ANKRD49 was increased in glioma tissues and that high expression of ANKRD49 was strongly associated with high disease grade and poor overall survival. To investigate the role of ANKRD49 in malignant glioma, lentivirus expressing shRNA targetting ANKRD49 was constructed in U251 and U87 malignant glioma cells. We demonstrated that ANKRD49 knockdown reduced the proliferation rate of U251 and U87 cells. Further mechanism analysis indicated that depletion of ANKRD49 led to the cell-cycle arrest and induced apoptosis in U251 and U87 cells. ANKRD49 knockdown also changed the expression of key effectors that are involved in stress response, cell cycle, and apoptosis, including p-HSP27 (heat shock protein 27), p-Smad2 (SMAD family member 2), p-p53, p-p38, p-MAPK (mitogen-activated protein kinase), p-SAPK/JNK (stress-activated protein kinase/c-jun n-terminal kinase), cleveagated Caspase-7, p-Chk1 (checkpoint kinase 1), and p-eIF2a (eukaryotic translation initiation factor 2a). Taken together, our findings implicate that ANKRD49 promotes the proliferation of human malignant glioma cells. ANKRD49 maybe an attractive target for malignant glioma therapy.

scholarly journals Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions

2019 ◽  
Vol 20 (9) ◽  
pp. 2304 ◽  
Author(s):  
Sachiko Matsuhashi ◽  
M. Manirujjaman ◽  
Hiroshi Hamajima ◽  
Iwata Ozaki
Keyword(s):  
Tumor Suppressor ◽  
Ubiquitin Ligase ◽  
Gene Mutations ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Control Mechanisms ◽  
Inflammatory Conditions ◽  
Binding Partners ◽  
Factor Eif4a ◽  
Pdcd4 Protein

PDCD4 is a novel tumor suppressor to show multi-functions inhibiting cell growth, tumor invasion, metastasis, and inducing apoptosis. PDCD4 protein binds to the translation initiation factor eIF4A, some transcription factors, and many other factors and modulates the function of the binding partners. PDCD4 downregulation stimulates and PDCD4 upregulation inhibits the TPA-induced transformation of cells. However, PDCD4 gene mutations have not been found in tumor cells but gene expression was post transcriptionally downregulated by micro environmental factors such as growth factors and interleukins. In this review, we focus on the suppression mechanisms of PDCD4 protein that is induced by the tumor promotors EGF and TPA, and in the inflammatory conditions. PDCD4-protein is phosphorylated at 2 serines in the SCFβTRCP ubiquitin ligase binding sequences via EGF and/or TPA induced signaling pathway, ubiquitinated, by the ubiquitin ligase and degraded in the proteasome system. The PDCD4 protein synthesis is inhibited by microRNAs including miR21.

4E-Binding Protein 1 (4E-BP1) in CD34+ Cells as Measured by Quantitative Flow Cytometry Is an Independent Prognostic Factor in Patients with Acute Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2772-2772
Author(s):  
M. Gorre ◽  
I. Jilani ◽  
R. Chang ◽  
J. Bareng ◽  
H. Chan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Binding Protein ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Mtor Inhibition ◽  
Cd34 Cells ◽  
Acute Myeloid

Abstract The mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in the regulation of cell growth and proliferation. Once activated, mTOR can phosphorylate its downstream targets. One of these targets is the 4E-binding protein 1 (4E-BP1), which is phosphorylated and inactivated by mTOR in response to a growth signal. Phospho-4E-BP1 dissociates from the eukaryotic initiation factor 4E (eIF-4E), a translation initiation factor that subsequently binds the cap structure of 5′ mRNAs and initiates the translation of transcripts encoding genes involved in cell cycle control. Rapamycin and its analogs are immunosuppressant drugs that exert their activity by specific inhibition of mTOR. mTOR inhibition induces cell cycle arrest not only in normal lymphocytes but also in malignant cells. Using flow cytometry, we quantified the levels of 4E-BP1 and phosopho-4E-BP1 in CD34+ and CD3+ cells from bone marrow samples collected from patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We then measured the antibody binding capacity of 100 CD34+ or CD3+ cells using QuantiBRITE and PE (phycoerythrin)-labeled antibodies in a 1:1 ratio. We demonstrated that CD34+ cells express significantly higher levels of 4E-BP1 (P=0.005) and phosphor-4E-BP1 (P=0.0001) as compared with CD3+ cells in patients with AML (n=49). In contrast, there was no significant difference in the levels of 4E-BP1 or phospho-4E-BP1 between CD34+ and CD3+ cells in patients with MDS (n=15). More importantly, in patients with AML, high expression of 4E-BP1 in CD34+ cells was associated with shorter survival (P=0.003) as well as shorter complete remission duration (CRD) (P=0.03). This association between survival and levels of 4E-BP1 was independent of cytogenetic abnormalities in this group of patients. This data not only suggests that the 4E-BP1 level, as measured in the CD34+ cells, can be an important prognostic indicator in AML but also suggests that 4E-BP1 plays a role in the biology of AML. Furthermore, targeting 4E-BP1 by mTOR inhibitors, or other means of down modulating 4E-BP1 levels, is a rational therapeutic approach in AML. Figure Figure

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 Regulation of the cell-cycle-dependent internal ribosome entry site of the PITSLRE protein kinase: roles of Unr (upstream of N-ras) protein and phosphorylated translation initiation factor eIF-2α

2004 ◽  
Vol 385 (1) ◽  
pp. 155-163 ◽  
Author(s):  
Sandrine A. TINTON ◽  
Bert SCHEPENS ◽  
Yanik BRUYNOOGHE ◽  
Rudi BEYAERT ◽  
Sigrid CORNELIS
Keyword(s):  
Cell Cycle ◽  
Internal Ribosome Entry Site ◽  
Encephalomyocarditis Virus ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Α Subunit ◽  
Initiation Of Translation ◽  
Cycle Dependent

The PITSLRE kinases belong to the large family of cyclin-dependent protein kinases. Their function has been related to cell-cycle regulation, splicing and apoptosis. We have previously shown that the open reading frame of the p110PITSLRE transcript contains an IRES (internal ribosome entry site) that allows the expression of a smaller p58PITSLRE isoform during the G2/M stage of the cell cycle. In the present study we investigated further the role of cis- and trans-acting factors in the regulation of the PITSLRE IRES. Progressive deletion analysis showed that both a purine-rich sequence and a Unr (upstream of N-ras) consensus binding site are essential for PITSLRE IRES activity. In line with these observations, we demonstrate that the PITSLRE IRES interacts with the Unr protein, which is more prominently expressed at the G2/M stage of the cell cycle. We also show that phosphorylation of the α-subunit of the canonical initiation factor eIF-2 is increased at G2/M. Interestingly, phosphorylation of eIF-2α has a permissive effect on the efficiency of both the PITSLRE IRES and the ornithine decarboxylase IRES, two cell cycle-dependent IRESs, in mediating internal initiation of translation, whereas this was not observed with the viral EMCV (encephalomyocarditis virus) and HRV (human rhinovirus) IRESs.

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