Linking tRNA localization with activation of nutritional stress responses

Huynh, Lenguyen; Thangavel, Muthusamy; Chen, Timothy; Cottrell, Ryan; Mitchell, Joy Maria; Prætorius-Ibba, Mette

doi:10.4161/cc.9.15.12525

Cited by 33 publications

(30 citation statements)

References 36 publications

(45 reference statements)

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“…Indeed, a recent work reported accumulation of tRNAs in the nucleus due to down-regulation of their transportin, XPO-t, during nutrient deprivation (Huynh et al 2010). Together with this report, our work highlights the nuclear transport machineries as critical control units for proper cell cycle regulation.…”

Section: Brief Perspectives and Related Issues On Cell Cycle-associatsupporting

confidence: 53%

Global microRNA elevation by inducible Exportin 5 regulates cell cycle entry

Iwasaki

Kiga

Kayo

et al. 2013

RNA

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Proper regulation of gene expression during cell cycle entry ensures the successful completion of proliferation, avoiding risks such as carcinogenesis. The microRNA (miRNA) network is an emerging molecular system regulating multiple genetic pathways. We demonstrate here that the global elevation of miRNAs is critical for proper control of gene expression program during cell cycle entry. Strikingly, Exportin 5 (XPO5) is promptly induced during cell cycle entry by a PI3K-dependent post-transcriptional mechanism. Inhibition of XPO5 induction interfered with global miRNA elevation and resulted in a proliferation defect associated with delayed G1/S transition. During cell cycle entry, XPO5 therefore plays a paramount role as a critical molecular hub controlling the gene expression program through global regulation of miRNAs. Our data suggest that XPO5-mediated global miRNA elevation might be involved in a broad range of cellular events associated with cell cycle control.

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Section: Brief Perspectives and Related Issues On Cell Cycle-associatsupporting

confidence: 53%

Global microRNA elevation by inducible Exportin 5 regulates cell cycle entry

Iwasaki

Kiga

Kayo

et al. 2013

RNA

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“…Because the phenotypes observed in tcs3 mutants are remarkably similar to tor mutants (61) or some of its positive regulators (49,62), an inter-relationship between the function of these elements would be expected. It has been shown that reductions in cytoplasmic tRNAs reduce TORC1 activity (8), suggesting the existence of an uncharacterized molecular feedback mechanism between the upstream protein synthesis controller, TORC1, and the canonical structural decoding blocks, the tRNAs. Furthermore, we found that tcs3 mutants have a severe decrease in S6K phosphorylation, a direct target of TORC1, whereas tcs3 overexpression enhanced it.…”

Section: Discussionmentioning

confidence: 99%

“…Since then, tRNAs have been linked to diverse regulatory processes (2): uncharged tRNAs regulate gene expression in response to nutrient availability (3); tRNAs directly bind cytochrome c inhibiting apoptosis (4); reduced levels of the initiator tRNA (tRNA i Met ) represses cell growth in yeast (5) and it is a limiting factor for growth in mammalian cells (6) and whole organism growth in Drosophila (7). Additionally, cytoplasmic tRNA availability has been shown to influence TORC1 2 (target of rapamycin complex 1) activity (8). Altogether these results reveal that in eukaryotic cells tRNAs are not only passive decoders of genetic information but also act as key regulators.…”

mentioning

confidence: 99%

The Levels of a Universally Conserved tRNA Modification Regulate Cell Growth

Rojas-Benítez

Thiaville

Crécy‐Lagard

et al. 2015

Journal of Biological Chemistry

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Background: Post-transcriptional modification of N 6 -threonylcarbamoyl-adenosine (t 6 A) is required for decoding function of tRNAs that pair A-starting codons. Results: t 6 A-modified tRNAs are required for growth, to modulate TOR activity and translation efficiency. Conclusion: Levels of t 6 A-modified tRNAs establish growth potential in eukaryotes. Significance: Recognition in eukaryotes of a conserved mechanism of growth control that relies on tRNA post-transcriptional modification.

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“…None of these proteins changed in response to GCN2 activation (data not shown). GCN2, liver injury and fibrosis E Arriazu et al GCN2 activation induced by amino acid restriction 24 or tRNA accumulation 25 has been shown to cause autophagy in different cell types. The role of autophagy in liver injury is complex.…”

Section: Discussionmentioning

confidence: 99%

GCN2 kinase is a key regulator of fibrogenesis and acute and chronic liver injury induced by carbon tetrachloride in mice

Arriazu

López-Zabalza

Leung

et al. 2013

Laboratory Investigation

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General control nonderepresible 2 (GCN2) is a highly conserved cytosolic kinase that modulates a complex response for coping with the stress owing to lack of amino acids. GCN2 has been recently shown to be involved in the regulation of metabolic balance and lipid degradation rate in the liver. We hypothesized that GCN2 could have a role in in hepatic fibrogenesis and in the response to acute or chronic liver injury. Activation of GCN2 in primary or immortalized human hepatic stellate cells by incubation with medium lacking the essential amino acid histidine correlated with decreased levels of collagen type I protein and mRNA, suggesting an antifibrogenic effect of GCN2. In vivo studies with Gcn2 knockout mice (Gcn2 À / À ) showed increased susceptibility to both acute or chronic liver damage induced by CCl 4 , as shown by higher alanine aminotransferase and aspartate aminotransferase activities, increased necrosis and higher inflammatory infiltrates compared with wild-type mice (WT). Chronic CCl 4 treatment increased deposition of interstitial collagen type I more in Gcn2 À / À mice than in WT mice. Col1a1 and col1a2 mRNA levels also increased in CCl 4 -treated Gcn2 À / À mice compared with WT mice. These results suggest that GCN2 is a key regulator of the fibrogenic response to liver injury.

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Linking tRNA localization with activation of nutritional stress responses

Cited by 33 publications

References 36 publications

Global microRNA elevation by inducible Exportin 5 regulates cell cycle entry

Global microRNA elevation by inducible Exportin 5 regulates cell cycle entry

The Levels of a Universally Conserved tRNA Modification Regulate Cell Growth

GCN2 kinase is a key regulator of fibrogenesis and acute and chronic liver injury induced by carbon tetrachloride in mice

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