Multiple amino acid sensing inputs to mTORC1

Shimobayashi, Mitsugu; Hall, Michael N.

doi:10.1038/cr.2015.146

Cited by 189 publications

(179 citation statements)

References 121 publications

(189 reference statements)

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“…This work adds a significant new dimension to the paradigm in which mTOR is mostly studied for its activation by growth factor-activated membrane receptors and nutrient availability (Menon and Manning 2008;Laplante and Sabatini 2013;Shimobayashi and Hall 2016). Furthermore, specific inhibition of RNA Pol II-driven transcription demonstrated that cytoplasmic mTOR activity alone is not sufficient for the androgenmediated rewiring of PCa cell metabolism.…”

Section: Discussionmentioning

confidence: 98%

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

et al. 2017

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Androgen receptor (AR) signaling reprograms cellular metabolism to support prostate cancer (PCa) growth and survival. Another key regulator of cellular metabolism is mTOR, a kinase found in diverse protein complexes and cellular localizations, including the nucleus. However, whether nuclear mTOR plays a role in PCa progression and participates in direct transcriptional cross-talk with the AR is unknown. Here, via the intersection of gene expression, genomic, and metabolic studies, we reveal the existence of a nuclear mTOR-AR transcriptional axis integral to the metabolic rewiring of PCa cells. Androgens reprogram mTOR-chromatin associations in an AR-dependent manner in which activation of mTOR-dependent metabolic gene networks is essential for androgeninduced aerobic glycolysis and mitochondrial respiration. In models of castration-resistant PCa cells, mTOR was capable of transcriptionally regulating metabolic gene programs in the absence of androgens, highlighting a potential novel castration resistance mechanism to sustain cell metabolism even without a functional AR. Remarkably, we demonstrate that increased mTOR nuclear localization is indicative of poor prognosis in patients, with the highest levels detected in castration-resistant PCa tumors and metastases. Identification of a functional mTOR targeted multigene signature robustly discriminates between normal prostate tissues, primary tumors, and hormone refractory metastatic samples but is also predictive of cancer recurrence. This study thus underscores a paradigm shift from AR to nuclear mTOR as being the master transcriptional regulator of metabolism in PCa.

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Section: Discussionmentioning

confidence: 98%

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

et al. 2017

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“…The serine/threonine protein kinase TOR (target of rapamycin) is a central regulator of ribosome biogenesis. Both yeast and mammalian cells have two functionally different TOR complexes, TOR complex 1 (TORC1) and TOR complex 2 (TORC2); TORC1 is stimulated by amino acid sufficiency, and it responds to rapamycin to generate responses akin to those elicited by starvation and environmental stress such as hypoxia and DNA damage to reduce cell growth (180,181). TORC2 is rapamycin insensitive and controls the organization of the actin cytoskeleton (181)(182)(183).…”

Section: Hmo1 Coordinates Responses To Torc1 Signalingmentioning

confidence: 99%

Yeast HMO1: Linker Histone Reinvented

Panday

Grove

2017

Microbiol Mol Biol Rev

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SUMMARY Eukaryotic genomes are packaged in chromatin. The higher-order organization of nucleosome core particles is controlled by the association of the intervening linker DNA with either the linker histone H1 or high mobility group box (HMGB) proteins. While H1 is thought to stabilize the nucleosome by preventing DNA unwrapping, the DNA bending imposed by HMGB may propagate to the nucleosome to destabilize chromatin. For metazoan H1, chromatin compaction requires its lysine-rich C-terminal domain, a domain that is buried between globular domains in the previously characterized yeast Saccharomyces cerevisiae linker histone Hho1p. Here, we discuss the functions of S. cerevisiae HMO1, an HMGB family protein unique in containing a terminal lysine-rich domain and in stabilizing genomic DNA. On ribosomal DNA (rDNA) and genes encoding ribosomal proteins, HMO1 appears to exert its role primarily by stabilizing nucleosome-free regions or “fragile” nucleosomes. During replication, HMO1 likewise appears to ensure low nucleosome density at DNA junctions associated with the DNA damage response or the need for topoisomerases to resolve catenanes. Notably, HMO1 shares with the mammalian linker histone H1 the ability to stabilize chromatin, as evidenced by the absence of HMO1 creating a more dynamic chromatin environment that is more sensitive to nuclease digestion and in which chromatin-remodeling events associated with DNA double-strand break repair occur faster; such chromatin stabilization requires the lysine-rich extension of HMO1. Thus, HMO1 appears to have evolved a unique linker histone-like function involving the ability to stabilize both conventional nucleosome arrays as well as DNA regions characterized by low nucleosome density or the presence of noncanonical nucleosomes.

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“…Amino acid transporters mediate the exchange of amino acids from extracellular to intracellular space as amino acid carriers, with some acting as amino acid sensors (37). Solute carriers (SLCs) that transport amino acids across the plasma membrane include SLC family 7, member 5 (SLC7A5); SLC3A2; and SLC1A5 (38). Amino acids can activate the Rag GTPases directly (26).…”

Section: Upstream Regulation Of Mtorc1 By Nutrients and Other Factorsmentioning

confidence: 99%

Perspective: The Potential Role of Essential Amino Acids and the Mechanistic Target of Rapamycin Complex 1 (mTORC1) Pathway in the Pathogenesis of Child Stunting

Semba

Trehan

González-Freire

et al. 2016

Advances in Nutrition

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Stunting is the best summary measure of chronic malnutrition in children. Approximately one-quarter of children under age 5 worldwide are stunted. Lipid-based or micronutrient supplementation has little to no impact in reducing stunting, which suggests that other critical dietary nutrients are missing. A dietary pattern of poor-quality protein is associated with stunting. Stunted children have significantly lower circulating essential amino acids than do nonstunted children. Inadequate dietary intakes of essential amino acids could adversely affect growth, because amino acids are required for synthesis of proteins. The master growth regulation pathway, the mechanistic target of rapamycin complex 1 (mTORC1) pathway, is exquisitely sensitive to amino acid availability. mTORC1 integrates cues such as nutrients, growth factors, oxygen, and energy to regulate growth of bone, skeletal muscle, nervous system, gastrointestinal tract, hematopoietic cells, immune effector cells, organ size, and whole-body energy balance. mTORC1 represses protein and lipid synthesis and cell and organismal growth when amino acids are deficient. Over the past 4 decades, the main paradigm for child nutrition in developing countries has been micronutrient malnutrition, with relatively less attention paid to protein. In this Perspective, we present the view that essential amino acids and the mTORC1 pathway play a key role in child growth. The current assumption that total dietary protein intake is adequate for growth among most children in developing countries needs reevaluation. Adv Nutr 2016;7:853-65.

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Multiple amino acid sensing inputs to mTORC1

Cited by 189 publications

References 121 publications

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

Yeast HMO1: Linker Histone Reinvented

Perspective: The Potential Role of Essential Amino Acids and the Mechanistic Target of Rapamycin Complex 1 (mTORC1) Pathway in the Pathogenesis of Child Stunting

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