Role of translation initiation factor 4G in lifespan regulation and age-related health

Howard, Amber C.; Rogers, Aric N.

doi:10.1016/j.arr.2013.12.008

Cited by 24 publications

(25 citation statements)

References 95 publications

(160 reference statements)

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“…Emerging from the results was strong signal for six polymorphisms jointly associating with starvation resistance and body mass, in DR flies and, separately, in flies reared on the AL diet (Table 1). These polymorphisms were in eIF4G2, a paralog of the nutrient-sensing factor eIF4G [43]; the ceramide synthase gene schlank ; and the Drosophila homolog of huntingtin, the gene underlying human Huntington’s disease (Table 1). These associations explained 8–12 % of the genetic variance in starvation resistance or body mass (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Cross-phenotype association tests uncover genes mediating nutrient response in Drosophila

et al. 2016

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BackgroundObesity-related diseases are major contributors to morbidity and mortality in the developed world. Molecular diagnostics and targets of therapies to combat nutritional imbalance are urgently needed in the clinic. Invertebrate animals have been a cornerstone of basic research efforts to dissect the genetics of metabolism and nutrient response. We set out to use fruit flies reared on restricted and nutrient-rich diets to identify genes associated with starvation resistance, body mass and composition, in a survey of genetic variation across the Drosophila Genetic Reference Panel (DGRP).ResultsWe measured starvation resistance, body weight and composition in DGRP lines on each of two diets and used several association mapping strategies to harness this panel of phenotypes for molecular insights. We tested DNA sequence variants for a relationship with single metabolic traits and with multiple traits at once, using a scheme for cross-phenotype association mapping; we focused our association tests on homologs of human disease genes and common polymorphisms; and we tested for gene-by-diet interactions. The results revealed gene and gene-by-diet associations between 17 variants and body mass, whole-body triglyceride and glucose content, or starvation resistance. Focused molecular experiments validated the role in body mass of an uncharacterized gene, CG43921 (which we rename heavyweight), and previously unknown functions for the diacylglycerol kinase rdgA, the huntingtin homolog htt, and the ceramide synthase schlank in nutrient-dependent body mass, starvation resistance, and lifespan.ConclusionsOur findings implicate a wealth of gene candidates in fly metabolism and nutrient response, and ascribe novel functions to htt, rdgA, hwt and schlank.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3137-9) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Cross-phenotype association tests uncover genes mediating nutrient response in Drosophila

et al. 2016

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“…Translation initiation switches from cap-dependent to IRESdependent mode during stress conditions such as hypoxia, vascular lesions, serum deprivation, -irradiation, apoptosis, growth arrest, and angiogenesis [35]. This shift is attributed to eIF2 phosphorylation, eIF4E-BP dephosphorylation, and eIF4G cleavage, any of which can inhibit canonical translation initiation [33,36]. Although the cellular IRES elements are activated under stress conditions, these IRESes differ in their requirement for eIFs.…”

Section: Role Of Eukaryotic Initiation Factors In Noncanonical Translmentioning

confidence: 99%

Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression

Sharma

Bressler

Patel

et al. 2016

Journal of Nucleic Acids

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Protein synthesis can be segmented into distinct phases comprising mRNA translation initiation, elongation, and termination. Translation initiation is a highly regulated and rate-limiting step of protein synthesis that requires more than 12 eukaryotic initiation factors (eIFs). Extensive evidence shows that the transcriptome and corresponding proteome do not invariably correlate with each other in a variety of contexts. In particular, translation of mRNAs specific to angiogenesis, tumor development, and apoptosis is altered during physiological and pathophysiological stress conditions. In cancer cells, the expression and functions of eIFs are hampered, resulting in the inhibition of global translation and enhancement of translation of subsets of mRNAs by alternative mechanisms. A precise understanding of mechanisms involving eukaryotic initiation factors leading to differential protein expression can help us to design better strategies to diagnose and treat cancer. The high spatial and temporal resolution of translation control can have an immediate effect on the microenvironment of the cell in comparison with changes in transcription. The dysregulation of mRNA translation mechanisms is increasingly being exploited as a target to treat cancer. In this review, we will focus on this context by describing both canonical and noncanonical roles of eIFs, which alter mRNA translation.

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“…The heterotrimeric eIF4F complex contains a scaffold protein (eIF4G), a DEAD (Asp-Glu-Ala-Asp)-box RNA helicase (eIF4A) and the capbinding protein eIF4E [17], which are involved in the recruitment of the ribosome to the mRNA [2,6]. Whereas eIF4E binds directly to the m 7 G-cap structure, eIF4G interacts with several additional protein partners, including eIF4E, eIF4A, eIF3, and the poly(A)-binding protein (PABP, also known as PABPC1) [18]. eIF3 is a large multisubunit protein complex that facilitates the recruitment of the 40S ribosomal subunit to the 5′ end of mRNA [19,20].…”

Section: Cap-dependent Mrna Translation Initiationmentioning

confidence: 99%

“…eIF4G is a modular scaffold that plays a critical role in the recruitment of the translational machinery to the mRNA and has been shown to be upregulated in a number of human malignancies [18]. In response to serum stimulation, eIF4G becomes phosphorylated on multiple residues in a manner that is dependent on mTORC1 [175], but the function of these phosphorylation events remains unknown.…”

Section: Additional Mtorc1 Targets Implicated In Mrna Translationmentioning

confidence: 99%

Translational control by oncogenic signaling pathways

Gao

Roux

2015

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Role of translation initiation factor 4G in lifespan regulation and age-related health

Cited by 24 publications

References 95 publications

Cross-phenotype association tests uncover genes mediating nutrient response in Drosophila

Cross-phenotype association tests uncover genes mediating nutrient response in Drosophila

Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression

Translational control by oncogenic signaling pathways

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