scholarly journals A novel role for IGF-1R in p53-mediated apoptosis through translational modulation of the p53-Mdm2 feedback loop

2007 ◽  
Vol 178 (6) ◽  
pp. 995-1007 ◽  
Author(s):  
Lei Xiong ◽  
Fei Kou ◽  
Ying Yang ◽  
Jiarui Wu
Keyword(s):  
Dna Damage ◽  
Translational Control ◽  
Messenger Rna ◽  
P53 Protein ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Cancer Cell Growth ◽  
Growth And Survival ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

Insulin-like growth factor 1 receptor (IGF-1R) is important in cancer cell growth and survival and has been implicated in cancer pathophysiology and treatment. Here we report a novel function for IGF-1R in p53-dependent apoptotic response. We show that inhibition or loss of IGF-1R activity reduces translational synthesis of p53 and Mdm2 protein. Notably, IGF-1R inhibition increases p53 protein stability by reducing p53 ubiquitination and maintains p53 at low levels by decreasing p53 synthesis, thus rendering p53 insensitive to stabilization after DNA damage. The accumulation and apoptosis of DNA-damage–induced p53 is therefore reduced in Igf-1r−/− mouse embryonic fibroblasts or tumor cells treated with the IGF-1R inhibitor. Furthermore, we find that inhibition of IGF-1R reduces p53 and Mdm2 translation through a gene-specific mechanism mediated by the respective 5′ untranslated region of p53 and mdm2 messenger RNA. The eukaryotic translation initiation factor 4F complex is also involved in this translational inhibition. These results demonstrate an unexpected role for translational control by IGF-1R in p53-mediated apoptosis.

Cinobufagin Triggers Defects in Spindle Formation and Cap-Dependent Translation in Liver Cancer Cells by Inhibiting the AURKA-mTOR-eIF4E Axis

2020 ◽  
Vol 48 (03) ◽  
pp. 651-678
Author(s):  
Xiaohan Jin ◽  
Jiabao Wang ◽  
Shuang Zou ◽  
Ruicheng Xu ◽  
Jin Cao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chromosome Segregation ◽  
Translation Initiation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Tandem Mass ◽  
Eukaryotic Translation ◽  
Liver Cancer Cells ◽  
Anticancer Effects ◽  
Eukaryotic Translation Initiation

Cinobufagin is a Na+/K+-ATPase (NKA) inhibitor with excellent anticancer effects to prolong the survival of patients. The purpose of the present study was to clarify the underlying mechanism of the anticancer effects of cinobufagin using overexpression or inhibition of aurora kinase A (AURKA) signaling. First, high expression of Na+/K+-ATPase alpha 1 subunit (ATP1A1) and AURAK resulted in increased malignant transformation in hepatocellular carcinoma (HCC) patients using the cancer genome atlas (TCGA) data and tissue samples. After treatment with cinobufagin, we successfully screened 202, 249, and 335 changing expression proteins in Huh-7 cells under normal, overexpression, and inhibition of AURKA using tandem mass tags (TMT)-labeled quantitative proteomics coupled to 2D liquid chromatography-tandem mass spectrometry (LC-MS/MS). Bioinformatics analysis revealed that these molecules were closely associated with chromosome segregation, DNA damage, and regulation of translation processes. We further confirmed that cinobufagin induced DNA damage and chromosome segregation disorders and suppresses translational processing in oncogenes by decreasing the expression of AURKA, mechanistic target of rapamycin kinase (mTOR), p-mTOR, p-extracellular regulated protein kinases (ERK), eukaryotic translation initiation factor 4E (eIF4E), and p-eIF4E, while increasing the expression of p-eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) (S65, T37, T46, T45) and increasing the interaction between eIF4 and 4E-BP1. Our results suggested that cinobufagin performed an antitumor effects in liver cancer cells by inhibiting the AURKA-mTOR-eIF4E axis.

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 Inhibition of Eukaryotic Translation Initiation Factor 5A (eIF5A) Hypusination Suppress p53 Translation and Alters the Association of eIF5A to the Ribosomes

2020 ◽  
Vol 21 (13) ◽  
pp. 4583 ◽  
Author(s):  
Marianna Martella ◽  
Caterina Catalanotto ◽  
Claudio Talora ◽  
Anna La Teana ◽  
Paola Londei ◽  
...  
Keyword(s):  
Translation Initiation ◽  
De Novo ◽  
P53 Protein ◽  
Translation Initiation Factor ◽  
Cellular Stress Response ◽  
Initiation Factor ◽  
Eukaryotic Translation Initiation Factor ◽  
P53 Expression ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

The eukaryotic translation initiation factor 5A (eIF5A) is an essential protein for the viability of the cells whose proposed function is to prevent the stalling of the ribosomes during translation elongation. eIF5A activity requires a unique and functionally essential post-translational modification, the change of a lysine to hypusine. eIF5A is recognized as a promoter of cell proliferation, but it has also been suggested to induce apoptosis. To date, the precise molecular mechanism through which eIF5A affects these processes remains elusive. In the present study, we explored whether eIF5A is involved in controlling the stress-induced expression of the key cellular regulator p53. Our results show that treatment of HCT-116 colon cancer cells with the deoxyhypusine (DHS) inhibitor N1-guanyl-1,7-diamineheptane (GC7) caused both inhibition of eIF5A hypusination and a significant reduction of p53 expression in UV-treated cells, and that eIF5A controls p53 expression at the level of protein synthesis. Furthermore, we show that treatment with GC7 followed by UV-induced stress counteracts the pro-apoptotic process triggered by p53 up-regulation. More in general, the importance of eIF5A in the cellular stress response is illustrated by the finding that exposure to UV light promotes the binding of eIF5A to the ribosomes, whereas UV treatment complemented by the presence of GC7 inhibits such binding, allowing a decrease of de novo synthesis of p53 protein.

scholarly journals Lentivirus-mediated knockdown of eukaryotic translation initiation factor 3 subunit D inhibits proliferation of HCT116 colon cancer cells

2014 ◽  
Vol 34 (6) ◽  
Author(s):  
Xiaojun Yu ◽  
Bo’an Zheng ◽  
Rui Chai
Keyword(s):  
Colon Cancer ◽  
Translation Initiation ◽  
Colon Cancer Cell ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Colon Cancer Cells ◽  
Cancer Cell Growth ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation ◽  
Translation Initiation Factor 3

eIF3D is essential for colon cancer cell growth, and knockdown of eIF3D resulted in a significant reduction in cell proliferation probably due to activation of AMPKα, Bad, PRAS40, SAPK/JNK and GSK3β, as well as cleavage of PARP.

scholarly journals Established and Emerging Regulatory Roles of Eukaryotic Translation Initiation Factor 5B (eIF5B)

2021 ◽  
Vol 12 ◽  
Author(s):  
Prakash Amruth Raj Chukka ◽  
Stacey D. Wetmore ◽  
Nehal Thakor
Keyword(s):  
Translation Initiation ◽  
Translational Control ◽  
Translational Regulation ◽  
Eukaryotic Cell ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Cellular Mrnas ◽  
Eukaryotic Translation Initiation ◽  
Initiation Stage

Translational control (TC) is one the crucial steps that dictate gene expression and alter the outcome of physiological process like programmed cell death, metabolism, and proliferation in a eukaryotic cell. TC occurs mainly at the translation initiation stage. The initiation factor eIF5B tightly regulates global translation initiation and facilitates the expression of a subset of proteins involved in proliferation, inhibition of apoptosis, and immunosuppression under stress conditions. eIF5B enhances the expression of these survival proteins to allow cancer cells to metastasize and resist chemotherapy. Using eIF5B as a biomarker or drug target could help with diagnosis and improved prognosis, respectively. To achieve these goals, it is crucial to understand the role of eIF5B in translational regulation. This review recapitulates eIF5B’s regulatory roles in the translation initiation of viral mRNA as well as the cellular mRNAs in cancer and stressed eukaryotic cells.

Abstract 321: Deletion Of The Translational Repressors Eukaryotic Translation Initiation Factor 4e Binding Proteins 1 And 2 Protects Against Pressure Overload Induced Heart Failure

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
zhongbing lu ◽  
Xinli Hu ◽  
Yimin Huang ◽  
Xin Xu ◽  
Ping zhang ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Translational Control ◽  
Binding Proteins ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Double Knockout ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

Assembly of the translation initiation machinery is negatively regulated by the eukaryotic translation initiation factor 4E binding proteins, which sequester the mRNA cap-binding protein eIF4E, thus preventing assembly of an intact initiation complex. However, the role of translational control on the development of congestive heart failure (CHF) has not been systematically examined. Here we perturbed translational control in mice by knockout of both 4E binding protein 1 (Eif4ebp1) and 2 (Eif4ebp2) (designated as Eif4ebp1/2 double knockout) to study its impact on left ventricular hypertrophy and CHF resulting from transverse aortic constriction. Eif4ebp1/2 double knockout caused a modest increase in left ventricular mass under basal conditions. However, following transverse aortic constriction, Eif4ebp1/2 double knockout profoundly attenuated the development of CHF and its attendant mortality. Examination of candidate genes involved in the mechanism revealed increased expression of transcription factors for genes governing energy metabolism and mitochondrial biogenesis with corresponding increases in the expression of their target genes. Our data indicate that removing physiological restraints on translation initiation exerts a profound cardiac protective effect against pressure overload induced CHF, suggesting that method(s) to disrupt the function of the 4E binding proteins may be a novel therapeutic approach for preventing or treating CHF.

Translational control of the cdc25 cell cycle phosphatase: a molecular mechanism coupling mitosis to cell growth

1999 ◽  
Vol 112 (18) ◽  
pp. 3137-3146 ◽  
Author(s):  
R.R. Daga ◽  
J. Jimenez
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Translational Control ◽  
Cell Mass ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Eukaryotic Mrnas ◽  
Eukaryotic Translation Initiation ◽  
Yeast Mutants

The eukaryotic translation initiation factor 4A (eIF4A) is an RNA helicase required for translation initiation of eukaryotic mRNAs. By engineering fission yeast mutants with diminished eIF4A activity, we have found that translation of cdc25 mRNAs (a dosage-dependent activator of mitosis in all eukaryotic cells) is particularly sensitive to limitations of protein synthesis mediated by limited eIF4A activity. Genetic and biochemical analysis indicated that a rate-limited translation initiation of cdc25 mRNAs, exerted throughout its unusual 5′ untranslated leader, acts as a molecular sensor to ensure that a minimum cell mass (protein synthesis) is attained before mitosis occurs. The Cdc13 cyclin B is also among the limited pool of proteins whose translation is sensitive to reduced translation initiation activity. Interestingly, the 5′ leader sequences of cdc25 and cdc13 mRNAs have conserved features which are unusual in other yeast mRNAs, suggesting that common mechanisms operate in the expression of these two key mitotic activators at the translational level.

scholarly journals Novel N7-Arylmethyl Substituted Dinucleotide mRNA 5′ cap Analogs: Synthesis and Evaluation as Modulators of Translation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1941
Author(s):  
Radoslaw Wojcik ◽  
Marek R. Baranowski ◽  
Lukasz Markiewicz ◽  
Dorota Kubacka ◽  
Marcelina Bednarczyk ◽  
...  
Keyword(s):  
Messenger Rna ◽  
A549 Cells ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Potential Applications ◽  
Eukaryotic Translation Initiation ◽  
Translational Inhibition

Dinucleotide analogs of the messenger RNA cap (m7GpppN) are useful research tools and have potential applications as translational inhibitors or reagents for modification of in vitro transcribed mRNAs. It has been previously reported that replacing the methyl group at the N7-position with benzyl (Bn) produces a dinucleotide cap with superior properties. Here, we followed up on this finding by synthesizing 17 novel Bn7GpppG analogs and determining their structure–activity relationship regarding translation and translational inhibition. The compounds were prepared in two steps, including selective N7-alkylation of guanosine 5′-monophosphate by arylmethyl bromide followed by coupling with imidazole-activated GDP, with total yields varying from 22% to 62%. The compounds were then evaluated by determining their affinity for eukaryotic translation initiation factor 4E (eIF4E), testing their susceptibility to decapping pyrophosphatase, DcpS—which is most likely the major cellular enzyme targeting this type of compound—and determining their translation inhibitory properties in vitro. We also synthesized mRNAs capped with the evaluated compounds and tested their translational properties in A549 cells. Our studies identified N7-(4-halogenbenzyl) substituents as promising modifications in the contexts of either mRNA translation or translational inhibition. Finally, to gain more insight into the consequences at the molecular level of N7-benzylation of the mRNA cap, we determined the crystal structures of three compounds with eIF4E.

scholarly journals Eukaryotic Translation Initiation Factor 5 Is Critical for Integrity of the Scanning Preinitiation Complex and Accurate Control of GCN4 Translation

2005 ◽  
Vol 25 (13) ◽  
pp. 5480-5491 ◽  
Author(s):  
Chingakham Ranjit Singh ◽  
Cynthia Curtis ◽  
Yasufumi Yamamoto ◽  
Nathan S. Hall ◽  
Dustin S. Kruse ◽  
...  
Keyword(s):  
Amino Acid ◽  
Translation Initiation ◽  
Translational Control ◽  
Point Mutations ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Preinitiation Complex ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

ABSTRACT The integrity of eukaryotic translation initiation factor (eIF) interactions in ribosomal preinitiation complexes is critical for the proper regulation of GCN4 mRNA translation in response to amino acid availability. Increased phosphorylation of eIF2 under amino acid starvation conditions leads to a corresponding increase in GCN4 mRNA translation. The carboxyl-terminal domain (CTD) of eIF5 (eIF5-CTD) has been identified as a potential nucleation site for preinitiation complex assembly. To further characterize eIF5 and delineate its role in GCN4 translational control, we isolated mutations leading to temperature sensitivity (Ts− phenotype) targeted at TIF5, the structural gene encoding eIF5 in yeast (Saccharomyces cerevisiae). Nine single point mutations were isolated, in addition to an allele in which the last 15 amino acids were deleted. The nine point mutations clustered in the eIF5-CTD, which contains two conserved aromatic/acidic boxes. Six of the point mutations derepressed GCN4 translation independent of eIF2 phosphorylation (Gcd− phenotype) at a permissive temperature, directly implicating eIF5-CTD in the eIF2/GTP/Met-tRNAi Met ternary complex binding process required for GCN4 translational control. In addition, stronger restriction of eIF5-CTD function at an elevated temperature led to failure to derepress GCN4 translation (Gcn− phenotype) in all of the mutants, most likely due to leaky scanning of the first upstream open reading frame of GCN4 mRNA. This latter result directly implicates eIF5-CTD in the process of accurate scanning for, or recognition of, AUG codons. Taken together, our results indicate that eIF5-CTD plays a critical role in both the assembly of the 43S complex and the postassembly process in the 48S complex, likely during the scanning process.

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