mTORC1 promotes cell growth via m6A-dependent mRNA degradation

Cho, Sungyun; Lee, Gina; Pickering, Brian F.; Jang, Cholsoon; Park, Jin H.; He, Long; Mathur, Lavina; Kim, Seung Soo; Jung, Sunhee; Tang, Hong-Wen; Monette, Sébastien; Rabinowitz, Joshua D.; Perrimon, Norbert; Jaffrey, Samie R.; Blenis, John

doi:10.1016/j.molcel.2021.03.010

Cited by 67 publications

(66 citation statements)

References 92 publications

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“…Additionally, controlling mRNA degradation is a major mechanism of m 6 A biology. m 6 A methylation could indirectly regulate the expression of certain molecules by degrading the mRNA of their co-regulators 60 . Whether the mRNA levels of SHP-2 suppressors are degraded by m 6 A methylation, thereby affecting SHP-2 protein expression, is also unknown.…”

Section: Discussionmentioning

confidence: 99%

METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells

et al. 2021

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Natural killer (NK) cells exert critical roles in anti-tumor immunity but how their functions are regulated by epitranscriptional modification (e.g., N6-methyladenosine (m6A) methylation) is unclear. Here we report decreased expression of the m6A “writer” METTL3 in tumor-infiltrating NK cells, and a positive correlation between protein expression levels of METTL3 and effector molecules in NK cells. Deletion of Mettl3 in NK cells alters the homeostasis of NK cells and inhibits NK cell infiltration and function in the tumor microenvironment, leading to accelerated tumor development and shortened survival in mice. The gene encoding SHP-2 is m6A modified, and its protein expression is decreased in METTL3-deficient NK cells. Reduced SHP-2 activity renders NK cells hyporesponsive to IL-15, which is associated with suppressed activation of the AKT and MAPK signaling pathway in METTL3-deficient NK cells. These findings show that m6A methylation safeguards the homeostasis and tumor immunosurveillance function of NK cells.

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Section: Discussionmentioning

confidence: 99%

METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells

et al. 2021

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“…mTOR signaling is involved in growth and disease through regulating gene transcription, mRNA degradation, protein synthesis, autophagy, lipid and carbohydrate metabolism (Giguere, 2018, Villa et al, 2021, Cho et al, 2021, Mossmann et al, 2018, Saxton and Sabatini, 2017). Further studies are required to elucidate how mTORC1 regulated by the Ragulator complex promotes the differentiation of the epiblast and ESCs.…”

Section: Discussionmentioning

confidence: 99%

Hbxip (Lamtor5) is essential for embryogenesis and regulates embryonic stem cell differentiation through activating mTORC1

Qin

Zhang

et al. 2022

Preprint

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Hbxip, also named Lamtor5, has been well characterized as a transcriptional coactivator in various cancers. However, the role of Hbxip in normal development remains unexplored. Here, we demonstrated that homozygous knockout of Hbxip leads to embryonic lethality, with retarded growth around E7.5. Using Hbxip knockout embryonic stem cells (ESCs), we showed that depletion of Hbxip compromises the self-renewal of ESCs, with reduced expression of pluripotency genes, reduced cell proliferation, and decreased colony forming capacity. In addition, Hbxip-/- ESCs are defective in differentiation, particularly ectodermal and mesodermal differentiation. Consistently, Hbxip-/- epiblast fails to differentiate properly, indicated by sustained expression of Oct4 in E8.5 Hbxip-/- epiblast. Mechanistically, in ESCs, Hbxip interacts with other components of the Ragulator complex, which is required for mTORC1 activation by amino acids. Importantly, ESCs depleted of Ragulator subunits, Lamtor3 or Lamtor4, display differentiation defects similar to those of Hbxip-/- ESCs. Moreover, Hbxip-/-, p14-/-, and p18-/- mice, lacking subunits of the Ragulator complex, also share similar phenotypes, embryonic lethality and retarded growth around E7-8. Thus, we conclude that Hbxip plays a pivotal role in the development and differentiation of the epiblast, as well as the self-renewal and differentiation of ESCs, through activating mTORC1 signaling.

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“…As cancers are caused by DNA mutation, alternative splicing of RNA, or DNA/RNA modification, NGS platforms thus plays critical roles in detecting and treating cancers. [28][29][30][31] While DNA sequencing techniques, including whole-genome, exome, and targeted sequencing (only focusing on a selection of genes of interest), detect gene mutations, RNA sequencing allows the detection of cancer-specific transcripts, posttranscriptional modifications, gene fusion, noncoding…”

Section: The Different Ngs Technology Platform Of Precision Medicinementioning

confidence: 99%

The importance of precision medicine in modern molecular oncology

Wang

Zheng

2021

Clinical Genetics

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With the rapid development of modern medical technology, information data modeling has been gradually applied to clinical diagnosis and treatment. Precision medicine is an important approach that focuses on individual patients in terms of their own characteristics, genomic information, proteomics and even social environments. Genome‐wide high‐throughput technologies, including DNA‐seq, RNA‐seq, exosome‐seq…, contribute enormous amounts of molecular data to aid in diagnosis and analysis. Here, we review the developmental history of different next‐generation sequencing platforms, introduce their applications in different tumor diagnosis and therapy, and further discuss the remaining challenges in precision medicine.

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mTORC1 promotes cell growth via m6A-dependent mRNA degradation

Cited by 67 publications

References 92 publications

METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells

METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells

Hbxip (Lamtor5) is essential for embryogenesis and regulates embryonic stem cell differentiation through activating mTORC1

The importance of precision medicine in modern molecular oncology

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