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The ability to translate genetic information into functional proteins is considered a landmark in evolution. Ribosomes have evolved to take on this responsibility and, although there are some differences in their molecular make-up, both prokaryotes and eukaryotes share a common structural architecture and similar underlying mechanisms of protein synthesis. Understanding ribosome function and biogenesis has been the focus of extensive research since the early days of their discovery. In the last decade however, new and unexpected roles have emerged that place deregulated ribosome biogenesis and protein synthesis at the crossroads of pathological settings, particularly cancer, revealing a set of novel cellular checkpoints. Moreover, it is also becoming evident that mTOR signaling, which regulates an array of anabolic processes, including ribosome biogenesis, is often exploited by cancer cells to sustain proliferation through the upregulation of global protein synthesis. The use of pharmacological agents that interfere with ribosome biogenesis and mTOR signaling has proven to be an effective strategy to control cancer development clinically. Here we discuss the most recent findings concerning the underlying mechanisms by which mTOR signaling controls ribosome production and the potential impact of ribosome biogenesis in tumor development. This article is part of a Special Issue entitled: Translation and Cancer. [ABSTRACT FROM AUTHOR]

Summary: Dysfunctional mTORC1 signaling is associated with a number of human pathologies owing to its central role in controlling cell growth, proliferation, and metabolism. Regulation of mTORC1 is achieved by the integration of multiple inputs, including those of mitogens, nutrients, and energy. It is thought that agents that increase the cellular AMP/ATP ratio, such as the antidiabetic biguanides metformin and phenformin, inhibit mTORC1 through AMPK activation of TSC1/2-dependent or -independent mechanisms. Unexpectedly, we found that biguanides inhibit mTORC1 signaling, not only in the absence of TSC1/2 but also in the absence of AMPK. Consistent with these observations, in two distinct preclinical models of cancer and diabetes, metformin acts to suppress mTORC1 signaling in an AMPK-independent manner. We found that the ability of biguanides to inhibit mTORC1 activation and signaling is, instead, dependent on the Rag GTPases. [Copyright &y& Elsevier]

Summary: Excess levels of circulating amino acids (AAs) play a causal role in specific human pathologies, including obesity and type 2 diabetes. Moreover, obesity and diabetes are contributing factors in the development of cancer, with recent studies suggesting that this link is mediated in part by AA activation of mammalian target of rapamycin (mTOR) Complex 1. AAs appear to mediate this response through class III phosphatidylinositol 3-kinase (PI3K), or human vacuolar protein sorting 34 (hVps34), rather than through the canonical class I PI3K pathway used by growth factors and hormones. Here we show that AAs induce a rise in intracellular Ca2+ ([Ca2+]i), which triggers mTOR Complex 1 and hVps34 activation. We demonstrate that the rise in [Ca2+]i increases the direct binding of Ca2+/calmodulin (CaM) to an evolutionarily conserved motif in hVps34 that is required for lipid kinase activity and increased mTOR Complex 1 signaling. These findings have important implications regarding the basic signaling mechanisms linking metabolic disorders with cancer progression. [Copyright &y& Elsevier]

Recent studies have shown that the nutrient input to the mTOR Complex1/S6K1 signaling pathway is mediated by class 3 PI3K or hVps34, the oldest member of the PI3K family. Moreover, studies to date would suggest that during the evolution of multicellular organisms this ancient branch of the pathway was merged with the growth-factor-hormone-controlled class 1 PI3K pathway at the level of mTOR Complex1 to control the development and growth of the organism. However, hVps34 also plays a role in the regulation of macroautophagy — the mechanism by which cells generate nutrients, such as amino acids, through the degradation of intracellular complexes, including mitochondria and ribosomes. These functions of hVps34 initially appear contradictory, since increased mTOR Complex1 activation is triggered by increased amino acid levels, while autophagy is triggered when cells are faced with amino acid deprivation. [Copyright &y& Elsevier]

Abstract: The tumor suppressor PTEN (phosphatase and tensin homolog) plays a critical role in the development and maintenance of the mammalian nervous system. Effects of inherited mutation of PTEN are highly variable and include macrocephaly, Lhermitte–Duclos disease (LDD) caused by a hamartomatous enlargement of the cerebellum, ataxia, seizures and autism, in addition to cancer predisposition. In the mouse, selective inactivation of Pten in post-mitotic granule neurons of the cerebellum and dentate gyrus showed that Pten was required for proper regulation of neuronal nuclear and soma size. Hypertrophy of Pten-deficient neurons required the activity of the serine–threonine kinase mTor. mTor is a master regulator of cell and organ growth which can trigger a cascade of downstream signaling pathways involving, in part, components of the translational machinery, including S6k1 and its substrate the ribosomal protein S6. Deletion of S6k1 in mice results in decreased size. Therefore, to determine the relative contribution of S6k1 to Pten-deficient neuronal hypertrophy in vivo, we crossed Pten brain-conditional knockouts with S6k1 null mice. Double mutant mice show no reversion or improvement in their Pten-related size and neurological defects including enlarged cerebella and dentate gyri with increased size of neuronal nuclei and somata, ataxia, and premature death. The hypertrophic Pten/S6k1-deficient neurons contained high levels of phosphorylated S6, similar to Pten-deficient neurons, suggesting that the mTor/S6k/S6 branch of the pathway was still active. Thus, we conclude that S6k1 is not required to cause hypertrophy of Pten-deficient neurons. This study reveals a cell type-dependent role for S6k1 in PI3K-dependent hypertrophy. [Copyright &y& Elsevier]

Summary Cells adapt to nutrient and energy deprivation by inducing autophagy, which is regulated by the mammalian target of rapamycin (mTOR) and AMP-activated protein kinases (AMPKs). We found that cell metabolism significantly influences the ability to induce autophagy, with mitochondrial complex I function being an important factor in the initiation, amplitude, and duration of the response. We show that phenformin or genetic defects in complex I suppressed autophagy induced by mTOR inhibitors, whereas autophagy was enhanced by strategies that increased mitochondrial metabolism. We report that mTOR inhibitors significantly increased select phospholipids and mitochondrial-associated membranes (MAMs) in a complex I-dependent manner. We attribute the complex I autophagy defect to the inability to increase MAMs, limiting phosphatidylserine decarboxylase (PISD) activity and mitochondrial phosphatidylethanolamine (mtPE), which support autophagy. Our data reveal the dynamic and metabolic regulation of autophagy. Graphical Abstract Highlights • Phenformin, metformin, and mitochondrial complex I defects suppress autophagy • Defects in glycolysis and OXPHOS have opposing effects on autophagy • Autophagy is enhanced by a metabolic shift toward OXPHOS • Mitochondrial-associated membranes and mitochondrial PE support autophagy Autophagy is a survival response to starvation conditions, which inhibit the mTOR kinase. Thomas et al. demonstrate that autophagy induced by mTOR inhibitors is limited by phenformin and defects in OXPHOS but enhanced by strategies that increase mitochondrial energy and phospholipid metabolism. The therapeutic relevance of these findings is discussed. [ABSTRACT FROM AUTHOR]

The circuitous cell signalling pathways of hepatocytes comprise several factors that operate to downgrade or even interrupt the transmission of a given signal. These down-regulating influences are essential to keep cell proliferation and cell survival in check and if impaired, can alter a delicate balance in favour of cell proliferation. Each signalling pathway that has been implicated in carcinogenesis is influenced by both oncogenic factors that promote tumour growth when activated as well as tumour suppressor proteins that have to be impaired to favour tumour growth. This summary of the Tumour Suppressors in Liver Carcinogenesis Symposium held at the 2007 EASL Annual Meeting discusses four pathways with pre-eminent tumour suppressor activity, each involved in hepatocarcinogenesis: p53, mTOR, beta-catenin and hedgehog. [Copyright &y& Elsevier]

The excess of saturated free fatty acids, such as palmitic acid, that induces lipotoxicity in hepatocytes, has been implicated in the development of non-alcoholic fatty liver disease also associated with insulin resistance. By contrast, oleic acid, a monounsaturated fatty acid, attenuates the effects of palmitic acid. We evaluated whether palmitic acid is directly associated with both insulin resistance and lipoapoptosis in mouse and human hepatocytes and the impact of oleic acid in the molecular mechanisms that mediate both processes. In human and mouse hepatocytes palmitic acid at a lipotoxic concentration triggered early activation of endoplasmic reticulum (ER) stress-related kinases, induced the apoptotic transcription factor CHOP, activated caspase 3 and increased the percentage of apoptotic cells. These effects concurred with decreased IR/IRS1/Akt insulin pathway. Oleic acid suppressed the toxic effects of palmitic acid on ER stress activation, lipoapoptosis and insulin resistance. Besides, oleic acid suppressed palmitic acid-induced activation of S6K1. This protection was mimicked by pharmacological or genetic inhibition of S6K1 in hepatocytes. In conclusion, this is the first study highlighting the activation of S6K1 by palmitic acid as a common and novel mechanism by which its inhibition by oleic acid prevents ER stress, lipoapoptosis and insulin resistance in hepatocytes. [ABSTRACT FROM AUTHOR]

Summary: Earlier, we reported that S6K1 −/− mice have reduced body fat mass, have elevated rates of lipolysis, have severely decreased adipocyte size, and are resistant to high fat diet (HFD)-induced obesity. Here we report that adipocytes of S6K1 −/− mice on a HFD have the capacity to increase in size to a degree comparable to that of wild-type (WT) mice, but not in number, indicating an unexpected lesion in adipogenesis. Tracing this lesion revealed that S6K1 is dispensable for terminal adipocyte differentiation, but is involved in the commitment of embryonic stem cells to early adipocyte progenitors. We further show that absence of S6K1 attenuates the upregulation of transcription factors critical for commitment to adipogenesis. These results led to the conclusion that a lack of S6K1 impairs the generation of de novo adipocytes when mice are challenged with a HFD, consistent with a reduction in early adipocyte progenitors. [Copyright &y& Elsevier]