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YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity [Ribo-seq]

ABSTRACT: YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity [Ribo-seq]

PROVIDER: PRJNA930426 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23305131.fastq.gz	Fastqsanger.gz
	SRR23305132.fastq.gz	Fastqsanger.gz
	SRR23305133.fastq.gz	Fastqsanger.gz
	SRR23305134.fastq.gz	Fastqsanger.gz
	SRR23305135.fastq.gz	Fastqsanger.gz

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YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity [Ribo-seq]

Project description:The Hippo pathway downstream effectors YAP and TAZ display oncogenic potential via their transcriptional co-activator function, mediated primarily by binding to TEAD transcription factors. Many studies have focused on identifying YAP/TAZ-TEAD target genes, but their role in the regulation of protein synthesis has remained largely unexplored. Here we show that YAP activation is sufficient to overcome the global translation restriction of 5TOP-containing mRNAs, which is induced by serum deprivation and dependent on the inactivation of mTORC1. We found that YAP/TAZ repressed the expression of DDIT4, a negative regulator of mTORC1 whose expression is otherwise upregulated by serum deprivation. Forced expression of DDIT4 was sufficient to suppress translation and transformative potential of serum-unresponsive uveal melanoma cells, which harbor G protein mutations. Our findings highlight crosstalk between Hippo-YAP/TAZ and mTORC1 pathways in the regulation of translation and offer a new perspective towards understanding YAP/TAZ-driven malignancies.

2024-10-01 | GSE224263 | GEO

YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity [293AD]

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YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity [MCF10A]

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YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity

Project description:YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity

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Project description:YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity [293AD]

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YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity [MCF10A]

Project description:YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity [MCF10A]

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YAP overcomes restriction of translation induced by nutrient deprivation through restoration of mTORC1 activity

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-10-01 | GSE224264 | GEO

A bi-steric mTORC1-selective inhibitor overcomes drug resistance in breast cancer

Project description:A bi-steric mTORC1-selective inhibitor overcomes drug resistance in breast cancer

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A bi-steric mTORC1-selective inhibitor overcomes drug resistance in breast cancer

Project description:Activation of the PI3K-mTOR pathway is central to breast cancer pathogenesis including resistance to many targeted therapies. The mTOR kinase forms two distinct complexes, mTORC1 and mTORC2, and understanding which is required for the survival of malignant cells has been limited by tools to selectively and completely impair either subcomplex. To address this, we used RMC-6272, a bi-steric molecule with a rapamycin-like moiety linked to an mTOR active-site inhibitor that displays >25-fold selectivity for mTORC1 over mTORC2 substrates. Complete suppression of mTORC1 by RMC-6272 causes apoptosis in ER+/HER2- breast cancer cell lines, particularly in those that harbor mutations in PIK3CA or PTEN, due to inhibition of the rapamycin resistant, mTORC1 substrate 4EBP1 and reduction of the pro-survival protein MCL1. RMC-6272 reduced translation of ribosomal mRNAs, MYC target genes, and components of the CDK4/6 pathway, suggesting enhanced impairment of oncogenic pathways compared to the partial mTORC1 inhibitor everolimus. RMC-6272 maintained efficacy in hormone therapy-resistant acquired cell lines and patient derived xenografts (PDX), showed increased efficacy in CDK4/6 inhibitor treated acquired resistant cell lines versus their parental counterparts, and was efficacious in a PDX from a patient experiencing resistance to CDK4/6 inhibition. Bi-steric mTORC1-selective inhibition may be effective in overcoming multiple forms of therapy-resistance in ER+ breast cancers.

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TORSEL, a 4EBP1-based mTORC1 live-cell sensor, reveals nutrient-sensing targeting by histone deacetylase inhibitor

Project description:Mammalian or the mechanistic target of rapamycin complex 1 (mTORC1) is an effective therapeutic target for diseases such as cancer, diabetes, aging, and neurodegeneration. However, an efficient tool to monitor mTORC1 inhibition in living cells or tissues is lacking. We developed a genetically encoded mTORC1 sensor called TORSEL. This sensor changes its fluorescence pattern from diffuse to punctate when 4EBP1 dephosphorylation occurs and interacts with eIF4E. TORSEL can specifically sense physiological, pharmacological, and genetic inhibition of mTORC1 signaling in living cells and tissues. Importantly, TORSEL is a valuable tool for imaging-based visual screening of mTORC1 inhibitors. Using TORSEL, we identified histone deacetylase inhibitors that selectively block nutrient-sensing signaling to inhibit mTORC1. Therefore, TORSEL is a unique living cell sensor that efficiently detects the inhibition of mTORC1 activity, and histone deacetylase inhibitors such as panobinostat target mTORC1 signaling through amino acid sensing.

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