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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 January 2018) | Viewed by 98999

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Dr. Andrew R. Tee

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Guest Editor

Division of Cancer and Genetics, Cardiff University, Cardiff, UK
Interests: mTOR; protein translation; hypoxia; Tuberous Sclerosis Complex; autophagy; cancer; signalling; protein kinases; angiogenesis; mitochondrial biogenesis
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Mammalian cells have developed a highly intricate network of signalling pathways that control their growth while maintaining energy and nutrient homeostasis. Mechanistic target of rapamycin (mTOR) lies at the heart of a cell growth signalling nexus that is lysosomally located, relaying upstream grow signals while also sensing the energy and nutrient status of the cell. Only when nutrients and energy are in sufficient supply can mTOR turn on anabolic processes to build cellular biomass. The capacity of a cell to grow is restricted by the supply of pre-cursor molecules necessary to generate proteins, lipids and DNA. Intracellular amino acid levels of the cell are increased through amino acid uptake and de novo biosynthesis and is necessary for growth. However, during states of starvation the cell needs to efficiently recycle amino acids to maintain their growth status. The proteasome and autophagy play an instrumental role in recycling amino acids and are tightly regulated by mTOR to maintain amino acid homeostasis. To rapidly build biomass in the growth phases of the cell cycle, mTOR has a multifaceted role, driving the efficiency of ribosomes to translate mRNA into protein while also manufacturing more of the ribosomal machinery through ribosomal biogenesis. Anabolic processes needed for cellular growth are highly energy demanding, so mTOR enhances mitochondrial biogenesis to generate more mitochondria, ensuring that the cell has enough capacity to generate energy as the cell grows. The ability of mTOR to switch between states of anabolic growth and catabolic fasting is dynamically regulated and is intrinsically coupled with the energy senor, AMPK. In the disease setting, improper mTOR signalling leads uncontrolled cell growth and homeostasis is lost. This review series will explore the range of mTOR-regulated processes that governs cell growth. We will review our current understanding of the complexities of mTOR and knowledge gaps in this topical research area.

Dr. Andrew R. Tee
Guest Editor

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Keywords

cell growth
mTOR
protein translation
autophagy
lysosome
energy
metabolism
AMPK
ULK1
ribosomal biogenesis
mitochondrial biogenesis
nutrients
amino acids
S6K1
4E-BP1
signalling

Published Papers (14 papers)

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Research

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20 pages, 4930 KiB

Open AccessArticle

B-Myb Mediates Proliferation and Migration of Non-Small-Cell Lung Cancer via Suppressing IGFBP3

by Xiaoyan Fan, Yitao Wang, Tinghui Jiang, Wei Cai, Yuelei Jin, Yulong Niu, Huifang Zhu and Youquan Bu

Int. J. Mol. Sci. 2018, 19(5), 1479; https://doi.org/10.3390/ijms19051479 - 16 May 2018

Cited by 27 | Viewed by 4241

Abstract

B-Myb has been shown to play an important oncogenic role in several types of human cancers, including non-small-cell lung cancer (NSCLC). We previously found that B-Myb is aberrantly upregulated in NSCLC, and overexpression of B-Myb can significantly promote NSCLC cell growth and motility. In the present study, we have further investigated the therapeutic potential of B-Myb in NSCLC. Kaplan–Meier and Cox proportional hazards analysis indicated that high expression of B-Myb is significantly associated with poor prognosis in NSCLC patients. A loss-of-function study demonstrated that depletion of B-Myb resulted in significant inhibition of cell growth and delayed cell cycle progression in NSCLC cells. Notably, B-Myb depletion also decreased NSCLC cell migration and invasion ability as well as colony-forming ability. Moreover, an in vivo study demonstrated that B-Myb depletion caused significant inhibition of tumor growth in a NSCLC xenograft nude mouse model. A molecular mechanistic study by RNA-seq analysis revealed that B-Myb depletion led to deregulation of various downstream genes, including insulin-like growth factor binding protein 3 (IGFBP3). Overexpression of IGFBP3 suppressed the B-Myb-induced proliferation and migration, whereas knockdown of IGFBP3 significantly rescued the inhibited cell proliferation and motility caused by B-Myb siRNA (small interfering RNA). Expression and luciferase reporter assays revealed that B-Myb could directly suppress the expression of IGFBP3. Taken together, our results suggest that B-Myb functions as a tumor-promoting gene via suppressing IGFBP3 and could serve as a novel therapeutic target in NSCLC. Full article

(This article belongs to the Special Issue Cell Growth Regulation)

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22 pages, 5246 KiB

Open AccessArticle

Examining the Genetic Background of Porcine Muscle Growth and Development Based on Transcriptome and miRNAome Data

by Katarzyna Ropka-Molik, Klaudia Pawlina-Tyszko, Kacper Żukowski, Katarzyna Piórkowska, Grzegorz Żak, Artur Gurgul, Natalia Derebecka and Joanna Wesoły

Int. J. Mol. Sci. 2018, 19(4), 1208; https://doi.org/10.3390/ijms19041208 - 16 Apr 2018

Cited by 20 | Viewed by 4492

Abstract

Recently, selection in pigs has been focused on improving the lean meat content in carcasses; this focus has been most evident in breeds constituting a paternal component in breeding. Such sire-breeds are used to improve the meat quantity of cross-breed pig lines. However, even in one breed, a significant variation in the meatiness level can be observed. In the present study, the comprehensive analysis of genes and microRNA expression profiles in porcine muscle tissue was applied to identify the genetic background of meat content. The comparison was performed between whole gene expression and miRNA profiles of muscle tissue collected from two sire-line pig breeds (Pietrain, Hampshire). The RNA-seq approach allowed the identification of 627 and 416 differentially expressed genes (DEGs) between pig groups differing in terms of loin weight between Pietrain and Hampshire breeds, respectively. The comparison of miRNA profiles showed differential expression of 57 microRNAs for Hampshire and 34 miRNAs for Pietrain pigs. Next, 43 genes and 18 miRNAs were selected as differentially expressed in both breeds and potentially related to muscle development. According to Gene Ontology analysis, identified DEGs and microRNAs were involved in the regulation of the cell cycle, fatty acid biosynthesis and regulation of the actin cytoskeleton. The most deregulated pathways dependent on muscle mass were the Hippo signalling pathway connected with the TGF-β signalling pathway and controlling organ size via the regulation of ubiquitin-mediated proteolysis, cell proliferation and apoptosis. The identified target genes were also involved in pathways such as the FoxO signalling pathway, signalling pathways regulating pluripotency of stem cells and the PI3K-Akt signalling pathway. The obtained results indicate molecular mechanisms controlling porcine muscle growth and development. Identified genes (SOX2, SIRT1, KLF4, PAX6 and genes belonging to the transforming growth factor beta superfamily) could be considered candidate genes for determining muscle mass in pigs. Full article

(This article belongs to the Special Issue Cell Growth Regulation)

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23 pages, 14944 KiB

Open AccessArticle

The Coordinated Activities of nAChR and Wnt Signaling Regulate Intestinal Stem Cell Function in Mice

by Toshio Takahashi, Akira Shiraishi and Jun Murata

Int. J. Mol. Sci. 2018, 19(3), 738; https://doi.org/10.3390/ijms19030738 - 05 Mar 2018

Cited by 28 | Viewed by 6190

Abstract

Cholinergic signaling, which modulates cell activities via nicotinic and muscarinic acetylcholine receptors (n- and mAChRs) in response to internal or external stimuli, has been demonstrated in mammalian non-neuronal cells that synthesize acetylcholine (ACh). One of the major pathways of excitatory transmission in the enteric nervous system (ENS) is mediated by cholinergic transmission, with the transmitter ACh producing excitatory potentials in postsynaptic effector cells. In addition to ACh-synthesizing and ACh-metabolizing elements in the ENS, the presence of non-neuronal ACh machinery has been reported in epithelial cells of the small and large intestines of rats and humans. However, little is known about how non-neuronal ACh controls physiological function in the intestine. Here, experiments using crypt–villus organoids that lack nerve and immune cells in culture suggest that endogenous ACh is synthesized in the intestinal epithelium to drive organoid growth and differentiation through activation of nAChRs. Treatment of organoids with nicotine enhanced cell growth and the expression of marker genes for stem and epithelial cells. On the other hand, the nAChR antagonist mecamylamine strongly inhibited the growth and differentiation of organoids, suggesting the involvement of nAChRs in the regulation of proliferation and differentiation of Lgr5-positive stem cells. More specifically, RNA sequencing analysis revealed that Wnt5a expression was dramatically upregulated after nicotine treatment, and Wnt5a rescued organoid growth and differentiation in response to mecamylamine. Taken together, our results indicate that coordinated activities of nAChR and Wnt signaling maintain Lgr5-positive stem cell activity and balanced differentiation. Furthermore, we could clearly separate the two groups, neuronal ACh in the ENS and non-neuronal ACh in the intestinal epithelium. Dysfunction of the non-neuronal cholinergic system is involved in the pathogenesis of disease. The data will increase our understanding of the cholinergic properties of non-neuronal cells and lead to optimization of drug therapy. Full article

(This article belongs to the Special Issue Cell Growth Regulation)

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13 pages, 7502 KiB

Open AccessArticle

Regulation of Akt/FoxO3a/Skp2 Axis Is Critically Involved in Berberine-Induced Cell Cycle Arrest in Hepatocellular Carcinoma Cells

by Fanni Li, Xiwen Dong, Peng Lin and Jianli Jiang

Int. J. Mol. Sci. 2018, 19(2), 327; https://doi.org/10.3390/ijms19020327 - 23 Jan 2018

Cited by 47 | Viewed by 6104

Abstract

The maintenance of ordinal cell cycle phases is a critical biological process in cancer genesis, which is a crucial target for anti-cancer drugs. As an important natural isoquinoline alkaloid from Chinese herbal medicine, Berberine (BBR) has been reported to possess anti-cancer potentiality to induce cell cycle arrest in hepatocellular carcinoma cells (HCC). However, the underlying mechanism remains to be elucidated. In our present study, G0/G1 phase cell cycle arrest was observed in berberine-treated Huh-7 and HepG2 cells. Mechanically, we observed that BBR could deactivate the Akt pathway, which consequently suppressed the S-phase kinase-associated protein 2 (Skp2) expression and enhanced the expression and translocation of Forkhead box O3a (FoxO3a) into nucleus. The translocated FoxO3a on one hand could directly promote the transcription of cyclin-dependent kinase inhibitors (CDKIs) p21^Cip1 and p27^Kip1, on the other hand, it could repress Skp2 expression, both of which lead to up-regulation of p21^Cip1 and p27^Kip1, causing G0/G1 phase cell cycle arrest in HCC. In conclusion, BBR promotes the expression of CDKIs p21^Cip1 and p27^Kip1 via regulating the Akt/FoxO3a/Skp2 axis and further induces HCC G0/G1 phase cell cycle arrest. This research uncovered a new mechanism of an anti-cancer effect of BBR. Full article

(This article belongs to the Special Issue Cell Growth Regulation)

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Open AccessArticle

CDX2 Stimulates the Proliferation of Porcine Intestinal Epithelial Cells by Activating the mTORC1 and Wnt/β-Catenin Signaling Pathways

by Hong-Bo Fan, Zhen-Ya Zhai, Xiang-Guang Li, Chun-Qi Gao, Hui-Chao Yan, Zhe-Sheng Chen and Xiu-Qi Wang

Int. J. Mol. Sci. 2017, 18(11), 2447; https://doi.org/10.3390/ijms18112447 - 18 Nov 2017

Cited by 24 | Viewed by 5740

Abstract

Caudal type homeobox 2 (CDX2) is expressed in intestinal epithelial cells and plays a role in gut development and homeostasis by regulating cell proliferation. However, whether CDX2 cooperates with the mammalian target of rapamycin complex 1 (mTORC1) and Wnt/β-catenin signaling pathways to stimulate cell proliferation remains unknown. The objective of this study was to investigate the effect of CDX2 on the proliferation of porcine jejunum epithelial cells (IPEC-J2) and the correlation between CDX2, the mTORC1 and Wnt/β-catenin signaling pathways. CDX2 overexpression and knockdown cell culture models were established to explore the regulation of CDX2 on both pathways. Pathway-specific antagonists were used to verify the effects. The results showed that CDX2 overexpression increased IPEC-J2 cell proliferation and activated both the mTORC1 and Wnt/β-catenin pathways, and that CDX2 knockdown decreased cell proliferation and inhibited both pathways. Furthermore, the mTORC1 and Wnt/β-catenin pathway-specific antagonist rapamycin and XAV939 (3,5,7,8-tetrahydro-2-[4-(trifluoromethyl)]-4H –thiopyrano[4,3-d]pyrimidin-4-one) both suppressed the proliferation of IPEC-J2 cells overexpressing CDX2, and that the combination of rapamycin and XAV939 had an additive effect. Regardless of whether the cells were treated with rapamycin or XAV939 alone or in combination, both mTORC1 and Wnt/β-catenin pathways were down-regulated, accompanied by a decrease in CDX2 expression. Taken together, our data indicate that CDX2 stimulates porcine intestinal epithelial cell proliferation by activating the mTORC1 and Wnt/β-catenin signaling pathways. Full article

(This article belongs to the Special Issue Cell Growth Regulation)

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1877 KiB

Open AccessArticle

Rapamycin Maintains the Chondrocytic Phenotype and Interferes with Inflammatory Cytokine Induced Processes

by Andrea De Luna-Preitschopf, Hannes Zwickl, Stefan Nehrer, Markus Hengstschläger and Mario Mikula

Int. J. Mol. Sci. 2017, 18(7), 1494; https://doi.org/10.3390/ijms18071494 - 11 Jul 2017

Cited by 16 | Viewed by 4525

Abstract

Osteoarthritis (OA) is hallmarked by a progressive degradation of articular cartilage. Besides risk factors including trauma, obesity or genetic predisposition, inflammation has a major impact on the development of this chronic disease. During the course of inflammation, cytokines such as tumor necrosis factor-alpha(TNF-α) and interleukin (IL)-1β are secreted by activated chondrocytes as well as synovial cells and stimulate the production of other inflammatory cytokines and matrix degrading enzymes. The mTORC1 inhibitor rapamycin is a clinical approved immunosuppressant and several studies also verified its chondroprotective effects in OA. However, the effect of blocking the mechanistic target of rapamycin complex (mTORC)1 on the inflammatory status within OA is not well studied. Therefore, we aimed to investigate if inhibition of mTORC1 by rapamycin can preserve and sustain chondrocytes in an inflammatory environment. Patient-derived chondrocytes were cultured in media supplemented with or without the mTORC1 inhibitor rapamycin. To establish an inflammatory environment, either TNF-α or IL-1β was added to the media (=OA-model). The chondroprotective and anti-inflammatory effects of rapamycin were evaluated using sulfated glycosaminoglycan (sGAG) release assay, Caspase 3/7 activity assay, lactate dehydrogenase (LDH) assay and quantitative real time polymerase chain reaction (PCR). Blocking mTORC1 by rapamycin reduced the release and therefore degradation of sGAGs, which are components of the extracellular matrix secreted by chondrocytes. Furthermore, blocking mTORC1 in OA chondrocytes resulted in an enhanced expression of the main chondrogenic markers. Rapamycin was able to protect chondrocytes from cell death in an OA-model shown by reduced Caspase 3/7 activity and diminished LDH release. Furthermore, inhibition of mTORC1 preserved the chondrogenic phenotype of OA chondrocytes, but also reduced inflammatory processes within the OA-model. This study highlights that blocking mTORC1 is a new and promising approach for treating OA. Low side effects make rapamycin an attractive implementation to existing therapeutic strategies. We showed that rapamycin’s chondroprotective property might be due to an interference with IL-1β triggered inflammatory processes. Full article

(This article belongs to the Special Issue Cell Growth Regulation)

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Open AccessArticle

Knockout of Murine Mamld1 Impairs Testicular Growth and Daily Sperm Production but Permits Normal Postnatal Androgen Production and Fertility

by Mami Miyado, Kaoru Yoshida, Kenji Miyado, Momori Katsumi, Kazuki Saito, Shigeru Nakamura, Tsutomu Ogata and Maki Fukami

Int. J. Mol. Sci. 2017, 18(6), 1300; https://doi.org/10.3390/ijms18061300 - 19 Jun 2017

Cited by 13 | Viewed by 4880

Abstract

MAMLD1 has been implicated in testicular function in both human and mouse fetuses. Although three patients with MAMLD1 mutations were reported to have hypergonadotropic hypogonadism in their teens, the functional significance of MAMLD1 in the postnatal testis remains unclear. Here, we analyzed the phenotype of Mamld1 knockout (KO) male mice at reproductive ages. The reproductive organs of KO male mice were morphologically unremarkable, except for relatively small testes. Seminiferous tubule size and number of proliferating spermatogonia/spermatocytes were reduced in the KO testis. Daily sperm production of KO mice was mildly attenuated, whereas total sperm counts in epididymal semen remained normal. Sperm motility and morphology, as well as androgen levels in serum and testicular tissues and the number of pups born from cross-mated wildtype (WT) female mice, were comparable between WT and KO male mice. These results indicate that MAMLD1 contributes to the maintenance of postnatal testicular growth and daily sperm production but is dispensable for androgen biosynthesis and fertility. MAMLD1 likely plays supporting roles in multiple and continuous steps of male reproduction. Full article

(This article belongs to the Special Issue Cell Growth Regulation)

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Review

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16 pages, 1004 KiB

Open AccessReview

Role of mTOR Complexes in Neurogenesis

by Francesca LiCausi and Nathaniel W. Hartman

Int. J. Mol. Sci. 2018, 19(5), 1544; https://doi.org/10.3390/ijms19051544 - 22 May 2018

Cited by 95 | Viewed by 10667

Abstract

Dysregulation of neural stem cells (NSCs) is associated with several neurodevelopmental disorders, including epilepsy and autism spectrum disorder. The mammalian target of rapamycin (mTOR) integrates the intracellular signals to control cell growth, nutrient metabolism, and protein translation. mTOR regulates many functions in the development of the brain, such as proliferation, differentiation, migration, and dendrite formation. In addition, mTOR is important in synaptic formation and plasticity. Abnormalities in mTOR activity is linked with severe deficits in nervous system development, including tumors, autism, and seizures. Dissecting the wide-ranging roles of mTOR activity during critical periods in development will greatly expand our understanding of neurogenesis. Full article

(This article belongs to the Special Issue Cell Growth Regulation)

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22 pages, 1442 KiB

Open AccessReview

mTOR Signaling and Neural Stem Cells: The Tuberous Sclerosis Complex Model

by Alice Polchi, Alessandro Magini, Danila Di Meo, Brunella Tancini and Carla Emiliani

Int. J. Mol. Sci. 2018, 19(5), 1474; https://doi.org/10.3390/ijms19051474 - 16 May 2018

Cited by 19 | Viewed by 6206

Abstract

The mechanistic target of rapamycin (mTOR), a serine-threonine kinase, plays a pivotal role in regulating cell growth and proliferation. Notably, a great deal of evidence indicates that mTOR signaling is also crucial in controlling proliferation and differentiation of several stem cell compartments. Consequently, dysregulation of the mTOR pathway is often associated with a variety of disease, such as cancer and metabolic and genetic disorders. For instance, hyperactivation of mTORC1 in neural stem cells (NSCs) is associated with the insurgence of neurological manifestation characterizing tuberous sclerosis complex (TSC). In this review, we survey the recent contributions of TSC physiopathology studies to understand the role of mTOR signaling in both neurogenesis and tumorigenesis and discuss how these new insights can contribute to developing new therapeutic strategies for neurological diseases and cancer. Full article

(This article belongs to the Special Issue Cell Growth Regulation)

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13 pages, 1089 KiB

Open AccessReview

The Target of Rapamycin and Mechanisms of Cell Growth

by Andrew R. Tee

Int. J. Mol. Sci. 2018, 19(3), 880; https://doi.org/10.3390/ijms19030880 - 16 Mar 2018

Cited by 54 | Viewed by 8751

Abstract

Mammalian target of rapamycin (mTOR, now referred to as mechanistic target of rapamycin) is considered as the master regulator of cell growth. A definition of cell growth is a build-up of cellular mass through the biosynthesis of macromolecules. mTOR regulation of cell growth and cell size is complex, involving tight regulation of both anabolic and catabolic processes. Upon a growth signal input, mTOR enhances a range of anabolic processes that coordinate the biosynthesis of macromolecules to build cellular biomass, while restricting catabolic processes such as autophagy. mTOR is highly dependent on the supply of nutrients and energy to promote cell growth, where the network of signalling pathways that influence mTOR activity ensures that energy and nutrient homeostasis are retained within the cell as they grow. As well as maintaining cell size, mTOR is fundamental in the regulation of organismal growth. This review examines the complexities of how mTOR complex 1 (mTORC1) enhances the cell’s capacity to synthesis de novo proteins required for cell growth. It also describes the discovery of mTORC1, the complexities of cell growth signalling involving nutrients and energy supply, as well as the multifaceted regulation of mTORC1 to orchestrate ribosomal biogenesis and protein translation. Full article

(This article belongs to the Special Issue Cell Growth Regulation)

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23 pages, 976 KiB

Open AccessReview

mTORC1 and Nutrient Homeostasis: The Central Role of the Lysosome

by Yoana Rabanal-Ruiz and Viktor I. Korolchuk

Int. J. Mol. Sci. 2018, 19(3), 818; https://doi.org/10.3390/ijms19030818 - 12 Mar 2018

Cited by 116 | Viewed by 11985

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) coordinates cellular growth and metabolism with environmental inputs to ensure that cells grow only under favourable conditions. When active, mTORC1 stimulates biosynthetic pathways including protein, lipid and nucleotide synthesis and inhibits cellular catabolism through repression of the autophagic pathway, thereby promoting cell growth and proliferation. The recruitment of mTORC1 to the lysosomal surface has been shown to be essential for its activation. This finding has significantly enhanced our knowledge of mTORC1 regulation and has focused the attention of the field on the lysosome as a signalling hub which coordinates several homeostatic pathways. The intriguing localisation of mTORC1 to the cellular organelle that plays a crucial role in catabolism enables mTORC1 to feedback to autophagy and lysosomal biogenesis, thus leading mTORC1 to enact precise spatial and temporal control of cell growth. This review will cover the signalling interactions which take place on the surface of lysosomes and the cross-talk which exists between mTORC1 activity and lysosomal function. Full article

(This article belongs to the Special Issue Cell Growth Regulation)

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31 pages, 3497 KiB

Open AccessReview

The Role of the Mammalian Target of Rapamycin (mTOR) in Pulmonary Fibrosis

by Jessica Lawrence and Richard Nho

Int. J. Mol. Sci. 2018, 19(3), 778; https://doi.org/10.3390/ijms19030778 - 08 Mar 2018

Cited by 130 | Viewed by 11744

Abstract

The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)-dependent pathway is one of the most integral pathways linked to cell metabolism, proliferation, differentiation, and survival. This pathway is dysregulated in a variety of diseases, including neoplasia, immune-mediated diseases, and fibroproliferative diseases such as pulmonary fibrosis. The mTOR kinase is frequently referred to as the master regulator of this pathway. Alterations in mTOR signaling are closely associated with dysregulation of autophagy, inflammation, and cell growth and survival, leading to the development of lung fibrosis. Inhibitors of mTOR have been widely studied in cancer therapy, as they may sensitize cancer cells to radiation therapy. Studies also suggest that mTOR inhibitors are promising modulators of fibroproliferative diseases such as idiopathic pulmonary fibrosis (IPF) and radiation-induced pulmonary fibrosis (RIPF). Therefore, mTOR represents an attractive and unique therapeutic target in pulmonary fibrosis. In this review, we discuss the pathological role of mTOR kinase in pulmonary fibrosis and examine how mTOR inhibitors may mitigate fibrotic progression. Full article

(This article belongs to the Special Issue Cell Growth Regulation)

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17 pages, 1056 KiB

Open AccessReview

The Role of mTOR in Neuroendocrine Tumors: Future Cornerstone of a Winning Strategy?

by Giuseppe Lamberti, Nicole Brighi, Ilaria Maggio, Lisa Manuzzi, Chiara Peterle, Valentina Ambrosini, Claudio Ricci, Riccardo Casadei and Davide Campana

Int. J. Mol. Sci. 2018, 19(3), 747; https://doi.org/10.3390/ijms19030747 - 06 Mar 2018

Cited by 41 | Viewed by 6342

Abstract

The mechanistic target of rapamycin (mTOR) is part of the phosphoinositide-3-kinase (PI3K)/protein kinase B (AkT)/mTOR pathway and owes its name to the inhibitory effect of rapamycin. The mTOR has a central converging role for many cell functions, serving as a sensor for extracellular signals from energy status and nutrients availability, growth factors, oxygen and stress. Thus, it also modulates switch to anabolic processes (protein and lipid synthesis) and autophagy, in order to regulate cell growth and proliferation. Given its functions in the cell, its deregulation is implicated in many human diseases, including cancer. Its predominant role in tumorigenesis and progression of neuroendocrine tumors (NETs), in particular, has been demonstrated in preclinical studies and late clinical trials. mTOR inhibition by everolimus is an established therapeutic target in NETs, but there are no identified predictive or prognostic factors. This review is focused on the role of mTOR and everolimus in NETs, from preclinical studies to major clinical trials, and future perspectives involving mTOR in the treatment of NETs. Full article

(This article belongs to the Special Issue Cell Growth Regulation)

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21 pages, 2211 KiB

Open AccessReview

Importance of ERK1/2 in Regulation of Protein Translation during Oocyte Meiosis

by Jaroslav Kalous, Anna Tetkova, Michal Kubelka and Andrej Susor

Int. J. Mol. Sci. 2018, 19(3), 698; https://doi.org/10.3390/ijms19030698 - 01 Mar 2018

Cited by 38 | Viewed by 6336

Abstract

Although the involvement of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway in the regulation of cytostatic factor (CSF) activity; as well as in microtubules organization during meiotic maturation of oocytes; has already been described in detail; rather less attention has been paid to the role of ERK1/2 in the regulation of mRNA translation. However; important data on the role of ERK1/2 in translation during oocyte meiosis have been documented. This review focuses on recent findings regarding the regulation of translation and the role of ERK1/2 in this process in the meiotic cycle of mammalian oocytes. The specific role of ERK1/2 in the regulation of mammalian target of rapamycin (mTOR); eukaryotic translation initiation factor 4E (eIF4E) and cytoplasmic polyadenylation element binding protein 1 (CPEB1) activity is addressed along with additional focus on the other key players involved in protein translation. Full article

(This article belongs to the Special Issue Cell Growth Regulation)

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