Nuclear Functions of TOR: Impact on Transcription and the Epigenome

Laribee, R. Nicholas; Weisman, Ronit

doi:10.3390/genes11060641

Cited by 29 publications

(27 citation statements)

References 177 publications

(294 reference statements)

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“…For example, mTORC1 phosphorylates the H3K9 demethylase jumonji domain containing 1C (JMJD1C) in a nutrient-dependent manner. The p-JMJD1C then interacts with the transcription factor USF-1 to demethylate H3K9me2 at genes promoting lipogenesis in the liver ( 44 , 45 ). However, whether mTOR induces BCAT1 expression by demethylating H3K9me2 and whether curcumin inhibits the expression level of BCAT1 by regulating methylation and acetylation of H3K9 require further investigation.…”

Section: Discussionmentioning

confidence: 99%

Curcumin induces apoptosis by inhibiting BCAT1 expression and mTOR signaling in cytarabine‑resistant myeloid leukemia cells

et al. 2021

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Cytarabine is a key chemotherapy drug for treating leukemia; however, chemotherapy-induced multidrug resistance is a major cause of therapy failure or tumor recurrence. Current medical treatment strategies still cannot address the issue of multidrug resistance phenotypes in the treatment of leukemia. Curcumin counteracts tumor development by inducing apoptosis in cytarabine-resistant acute myeloid leukemia cells. Branched-chain amino acid transaminase 1 (BCAT1), an aminotransferase enzyme, acts on branched-chain amino acids. Moreover, the aberrant expression of BCAT1 has been observed in numerous cancer cells, and BCAT1 serves a critical role in the progression of myeloid leukemia. BCAT1 can interfere with cancer cell proliferation by regulating mTOR-mediated mitochondrial biogenesis and function. The present study aimed to investigate whether curcumin induces apoptosis by regulating BCAT1 expression and mTOR signaling in cytarabine-resistant myeloid leukemia cells. Four leukemia cell lines and three primary myeloid leukemia cells were treated with curcumin, and the expression and activity of BCAT1 and mTOR were investigated by reverse transcription-quantitative PCR, western blotting and α-KG quantification assay. The results demonstrated that curcumin inhibited BCAT1 expression in Kasumi-1, KG-1, HL60, cytarabine-resistant HL60, and cytarabine-resistant primary myeloid leukemia cells. Notably, tetrahydrocurcumin, a major metabolite of curcumin, and cytarabine had no inhibitory effect on BCAT1 expression. Furthermore, BCAT1 and mTOR signaling may modulate each other in cytarabine-resistant HL60 cells. The present results indicated that curcumin may induce apoptosis by inhibiting the BCAT1 and mTOR pathways. Thus, understanding the mechanism underlying curcumin-induced apoptosis in cytarabine-resistant cells can support the development of novel drugs for leukemia.

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Section: Discussionmentioning

confidence: 99%

Curcumin induces apoptosis by inhibiting BCAT1 expression and mTOR signaling in cytarabine‑resistant myeloid leukemia cells

et al. 2021

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“…However, a REPTOR homologue or functionally related transcription factor in mammals and yeast is yet to be identified. The localisation of mTOR kinases and complexes is the focus of a recent review [ 46 ]. Here, we concentrate on examples of mTOR-dependent ageing-related transcriptional effects in diverse model systems from yeast to human cells ( Figure 2 ).…”

Section: Lifespan Effects Of Mtor Through Regulation Of Gene Transmentioning

confidence: 99%

The Target of Rapamycin Signalling Pathway in Ageing and Lifespan Regulation

Bjedov

Rallis

2020

Genes

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Ageing is a complex trait controlled by genes and the environment. The highly conserved mechanistic target of rapamycin signalling pathway (mTOR) is a major regulator of lifespan in all eukaryotes and is thought to be mediating some of the effects of dietary restriction. mTOR is a rheostat of energy sensing diverse inputs such as amino acids, oxygen, hormones, and stress and regulates lifespan by tuning cellular functions such as gene expression, ribosome biogenesis, proteostasis, and mitochondrial metabolism. Deregulation of the mTOR signalling pathway is implicated in multiple age-related diseases such as cancer, neurodegeneration, and auto-immunity. In this review, we briefly summarise some of the workings of mTOR in lifespan and ageing through the processes of transcription, translation, autophagy, and metabolism. A good understanding of the pathway’s outputs and connectivity is paramount towards our ability for genetic and pharmacological interventions for healthy ageing and amelioration of age-related disease.

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“…The protein kinase TOR is a conserved sensor of nutrient availability and energy status in eukaryotes, known to regulate many fundamental cellular processes, such as translation, autophagy and cell cycle (Saxton and Sabatini, 2017). In animals, since diet and nutrient exert transgenerational effect, correlations between TOR functions and epigenome variations started to be explored (Laribee and Weisman, 2020). Histone acetylation is the most characterized mark regulated by TOR signaling to control rDNA transcription.…”

Section: Introductionmentioning

confidence: 99%

“…Histone acetylation is the most characterized mark regulated by TOR signaling to control rDNA transcription. Recently, mammalian/mechanistic TOR complex 1 (mTORC1) was found to activate its canonical substrate S6K1 which further phosphorylates H2B to influence global histone methylation (Laribee and Weisman, 2020). Unlike in animals, little is known in plants to link TOR function to epigenetic modifications.…”

Section: Introductionmentioning

confidence: 99%

TOR represses stress responses through global regulation of H3K27 trimethylation in plants

Dong

Uslu

Berr

et al. 2021

Preprint

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Combinations of epigenetic modifications H3K4me3 and H3K27me3 implicate bistable feature which alternates between on and off state allowing rapid transcriptional changes upon external stimuli. Target of Rapamycin (TOR) functions as a central sensory hub to link a wide range of external stimuli to gene expression. However, the mechanisms underlying stimulus-specific transcriptional reprogramming by TOR remains elusive. Our in silico analysis in Arabidopsis demonstrates that TOR-repressed genes are associated with either bistable or silent chromatin domains. Both domains regulated by TOR signaling pathway are associated with high level of H3K27me3 deposited by CURLY LEAF (CLF) in specific context with LIKE HETEROCHROMATIN PROTEIN1 (LHP1). Chromatin remodeler SWI2/SNF2 ATPase BRAHMA (BRM) activates TOR-repressed genes only at bistable chromatin domains to rapidly induce biotic stress responses. Here we demonstrated both in silico and in vivo that TOR represses transcriptional stress responses through global maintenance of H3K27me3.

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Nuclear Functions of TOR: Impact on Transcription and the Epigenome

Cited by 29 publications

References 177 publications

Curcumin induces apoptosis by inhibiting BCAT1 expression and mTOR signaling in cytarabine‑resistant myeloid leukemia cells

Curcumin induces apoptosis by inhibiting BCAT1 expression and mTOR signaling in cytarabine‑resistant myeloid leukemia cells

The Target of Rapamycin Signalling Pathway in Ageing and Lifespan Regulation

TOR represses stress responses through global regulation of H3K27 trimethylation in plants

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