The nuclear import of ribosomal proteins is regulated by mTOR

Kazyken, Dubek; Kaz, Yelimbek; Kiyan, Vladimir; Zhylkibayev, Assylbek; Chen, Chien Hung; Agarwal, Nitin; Sarbassov, Dos D.

doi:10.18632/oncotarget.2473

Cited by 21 publications

(14 citation statements)

References 65 publications

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“…However, at this stage it is unclear how nutrient-dependent mTOR activity regulates TFEB nuclear export. Multiple studies have shown that mTOR localizes and functions in the nuclear compartment [31][32][33][34][35][36][37] . Therefore, it is possible that a nuclear pool of mTOR is responsible for TFEB phosphorylation and induction of nuclear export.…”

Section: Discussionmentioning

confidence: 99%

mTOR-dependent phosphorylation controls TFEB nuclear export

Napolitano

Esposito

Choi

et al. 2018

Preprint

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The transcriptional activation of catabolic processes during starvation is induced by the nuclear translocation and consequent activation of transcription factor EB (TFEB), a master modulator of autophagy and lysosomal biogenesis. However, how TFEB is inactivated upon nutrient re-feeding is currently unknown. Here we show that TFEB subcellular localization is dynamically controlled by its continuous shuttling between the cytosol and the nucleus, with the nuclear export representing a limiting step. TFEB nuclear export is mediated by CRM1 and is modulated by nutrient availability via mTOR-dependent hierarchical multisite phosphorylation of serines S142 and S138, which are localized in proximity of a nuclear export signal (NES). Our data reveal that modulation of TFEB nuclear export via phosphorylation plays a major role in the modulation of TFEB localization and activity.

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Section: Discussionmentioning

confidence: 99%

mTOR-dependent phosphorylation controls TFEB nuclear export

Napolitano

Esposito

Choi

et al. 2018

Preprint

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“…Unlike in yeast, mTOR is not considered to stimulate RP gene expression in mammals, instead exerting its effects on the level of translation (Powers and Walter 1999). Furthermore, nuclear abundance of RPs was recently suggested to be regulated by a subfraction of mTOR found at the nuclear envelope and complex bound to the nuclear import protein Ran Binding protein 2 (RanBP2) (Kazyken et al 2014). The number of identified 5'TOP mRNAs is growing, with recent studies estimating the existence of approximately 150-200 5'TOP mRNAs, exceeding the number of RPs originally suggested to make up this group (Yamashita et al 2008).…”

Section: Mtor In the Regulation Of Protein Synthesis And Ribosome Biomentioning

confidence: 99%

Resistance exercise training modulates acute gene expression during human skeletal muscle hypertrophy

Nader

Walden

Liu

et al. 2014

Journal of Applied Physiology

112

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We sought to determine whether acute resistance exercise (RE)-induced gene expression is modified by RE training. We studied the expression patterns of a select group of genes following an acute bout of RE in naïve and hypertrophying muscle. Thirteen untrained subjects underwent supervised RE training for 12 wk of the nondominant arm and performed an acute bout of RE 1 wk after the last bout of the training program (training+acute). The dominant arm was either unexercised (control) or subjected to the same acute exercise bout as the trained arm (acute RE). Following training, men (14.8 ± 2.8%; P < 0.05) and women (12.6 ± 2.4%; P < 0.05) underwent muscle hypertrophy with increases in dynamic strength in the trained arm (48.2 ± 5.4% and 72.1 ± 9.1%, respectively; P < 0.01). RE training resulted in attenuated anabolic signaling as reflected by a reduction in rpS6 phosphorylation following acute RE. Changes in mRNA levels of genes involved in hypertrophic growth, protein degradation, angiogenesis, and metabolism commonly expressed in both men and women was determined 4 h following acute RE. We show that RE training can modify acute RE-induced gene expression in a divergent and gene-specific manner even in genes belonging to the same ontology. Changes in gene expression following acute RE are multidimensional, and may not necessarily reflect the actual adaptive response taking place during the training process. Thus RE training can selectively modify the acute response to RE, thereby challenging the use of gene expression as a marker of exercise-induced adaptations.

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“…Our data indicates that mTOR and nutrient sensing regulate the localization of polκ, and this pathway more broadly is known to affect nuclear-cytoplasmic shuttling of multiple proteins (84)(85)(86)(87)(88)(89)(90)(91). For example, PI3K/Akt/mTOR signaling has been shown to prevent nuclear accumulation of glycogen synthase kinase 3β (GSK3β) such that inhibition of this pathway leads to a robust increase in nuclear GSK3β (89,90).…”

Section: Discussionmentioning

confidence: 93%

Regulation of the error-prone DNA polymerase polκ by oncogenic signaling and its contribution to drug resistance

Temprine¹,

Langdon

Mehta

et al. 2018

Preprint

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AbstractMutations in the proofreading domains of the replicative DNA polymerases polδ and polε are associated with elevated mutation rates in cancer, but the roles of other DNA polymerases in tumorigenesis remain poorly understood. One such polymerase is polκ, an enzyme that plays a key role in translesion synthesis. polκ contributes to cell survival in the face of DNA damage but can be highly mutagenic due to lack of a proofreading domain. Here we demonstrate that cancer cells under stress from oncogene inhibition upregulate polκ and shift its localization from the cytoplasm to the nucleus. This effect can be phenocopied by mTOR inhibition or glucose deprivation, analogous to stress-induced mutagenesis in E. coli whereby cell stress and nutrient deprivation can upregulate and activate DinB/pol IV (the bacterial orthologue of polκ). We find that cancer cells normally sequester polκ in the cytoplasm via exportin-1, likely to prevent excess mutagenesis from the error-prone nature of this polymerase. Subverting the normal nuclear-cytoplasmic shuttling by forced overexpression of nuclear polκ increases resistance of melanoma cells to the BRAFV600E inhibitor vemurafenib. This data suggests a mechanism by which cancer cells regulate the expression and localization of the error-prone polymerase polκ, abrogation of which can contribute to drug resistance.One Sentence Summary: Cancer cells under stress from oncogene or mTOR inhibition dysregulate the error-prone DNA polymerase polκ, which contributes to drug resistance in melanoma cells.

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The nuclear import of ribosomal proteins is regulated by mTOR

Cited by 21 publications

References 65 publications

mTOR-dependent phosphorylation controls TFEB nuclear export

mTOR-dependent phosphorylation controls TFEB nuclear export

Resistance exercise training modulates acute gene expression during human skeletal muscle hypertrophy

Regulation of the error-prone DNA polymerase polκ by oncogenic signaling and its contribution to drug resistance

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