File Name: mtor signaling in growth control and disease .zip
Review Free access Phone: Find articles by Kim, Y. Find articles by Guan, K. Published January 2, - More info. Nutrients, growth factors, and cellular energy levels are key determinants of cell growth and proliferation. Deregulation of mTOR signaling has been implicated in many human diseases, including diabetes, neurodegenerative diseases, and cancer 1.
The two kinase complexes have specific substrate preferences and therefore elicit distinct downstream signaling events to modulate cellular function. The mTOR signaling network. One of the well-established roles of mTORC1 is to promote anabolic cellular metabolism to supply the necessary building blocks for cell growth and proliferation.
Genetic mutations in hamartin or tuberin encoding TSC1 and TSC2, respectively cause tumor development in various tissues such as angiofibromas, angiomyolipomas, lymphangioleiomyomatosis, and renal cell carcinoma. Amino acids, which are essential components for protein synthesis, are also crucial regulators of mTORC1 reviewed in refs. RagA and RagB have high amino acid homology and are functionally redundant, and RagC and RagD are homologous and functionally redundant when they are expressed in the same cell.
In the presence of amino acids, the Rag GTPases are activated and recruit mTORC1 to the surface of the lysosome, where the kinase complex encounters its upstream effector Rheb, which activates the kinase complex through an undefined mechanism Recent studies suggest that other subcellular compartments such as stress granule and peroxisome also play important roles in mTORC1 signaling regulation in response to oxidative stress 39 , 40 , although the interplay of those subcellular compartments with lysosome in mTORC1 activation is not fully elucidated.
However, another study using conditional knockout mice shows that loss of RagA and RagB in cardiomyocytes causes lysosomal dysfunction due to deregulated lysosomal v-ATPase localization even though mTORC1 activation is not substantially affected The molecular mechanism of mTORC2 regulation by upstream effectors is largely unknown.
Again, the mechanism of how ribosomal association activates mTORC2 has yet to be revealed. Moreover, this model needs to be verified in other systems. Autophagy is the major cellular digestion process that removes damaged macromolecules and organelles. In addition, autophagy is critical to providing energy and molecular building blocks by recycling macromolecules in response to nutrient and environmental stress reviewed in ref.
The discovery by electron microscopy of vesicle structures containing amorphous materials and cytoplasmic organelles in the kidneys of newborn mice led to the introduction of autophagy in the late s 58 , About 20 years after that initial discovery, it was observed that amino acid deprivation is a potent autophagy inducer in cultured mammalian cells and in perfused rat livers 60 , As previously mentioned, amino acids are key regulators of mTORC1 activation.
Furthermore, most if not all autophagy induction conditions such as nutrient or growth factor deprivation and low cellular energy levels have been shown to inhibit mTORC1 activity. This suggests a tight, inverse coupling of autophagy induction and mTORC1 activation.
However, the mechanistic understanding of how mTORC1 regulates autophagy in mammalian cells is fairly recent Figure 2 and reviewed in refs. VPS34 forms multiple complexes and has critical roles in cellular vesicle trafficking and autophagy induction. Regulation of autophagy by mTORC1. Proper lysosome function is essential for autophagy completion. The transcriptional activity of TFEB is regulated by nutrient and phosphorylation-dependent cytoplasm-to-nucleus shuttling In conclusion, mTORC1 coordinates both anabolism and catabolism to meet the needs of cell growth.
In growing cells, high mTORC1 activity promotes biomolecule synthesis and simultaneously inhibits autophagy. Autophagy flux denotes the sum total of autophagic molecular events, from the induction of autophagy and autophagosome formation to the autolysosomal degradation and reformation of lysosome. Interestingly, although mTORC1 is inactivated during autophagy initiation, the kinase complex is reactivated by energy supplies generated by the degradation of autolysosomal products at the end of autophagy flux.
Its reactivation is required for the reformation of functional lysosomes, indicating the critical role of mTORC1 in the completion of autophagy flux As discussed above, it is not fully understood how mTORC2 activity is regulated.
Further studies are needed to determine whether mTORC2 can directly regulate autophagy. Autophagy is a cellular process essential for development and tissue homeostasis.
Autophagy is implicated in various physiologic and pathologic processes including exercise, metabolic adaptation, and disorders such as neurodegenerative diseases, infectious diseases, cardiovascular diseases, cancer, and aging , and thus pharmacologic modulation of autophagy is of great interest reviewed in refs. As a master regulator of cellular metabolism and autophagy, mTORC1 is an appealing pharmacologic target to manipulate autophagy. In fact, deregulation of mTORC1 has been implicated in diseases that are associated with autophagy defects 1 , and there are mTOR inhibitors already in clinical trials or approved for treatment of these diseases reviewed in refs.
There are also pharmacologic molecules that can induce or inhibit autophagy via mTOR-independent mechanisms For example, agents such as bafilomycin A1 and hydroxychloroquine that increase lysosomal pH can block autophagy flux by inhibiting autolysosomal formation. Such inhibitors could be combined with mTOR inhibitors to finely modulate autophagy flux.
In this section we discuss currently available mTOR inhibitors and their effects on autophagy. We also summarize some mTOR inhibitors and their use for autophagy induction in preclinical studies Table 1.
Rapamycin and rapalogs. Rapamycin was originally isolated from the soil bacterium Streptomyces hygroscopicus as an antifungal compound in , and was later shown to be a strong immunosuppressant with broad anti-proliferative effects in mammalian cells reviewed in ref. About 16 years after the isolation of rapamycin, an elegant yeast genetic screen to identify rapamycin-resistant genes led to the discovery of TOR1 and TOR2 Rapamycin forms a complex with FKB12 in the cell, and this complex specifically binds to mTORC1 and allosterically inhibits its kinase activity.
Because of its anti-proliferation effects, rapamycin has been thoroughly evaluated as a therapeutic drug for cancer. In addition, rapamycin has been used as an immunosuppressant for organ transplantation and a cell growth inhibitor for preventing restenosis. In order to improve the pharmacokinetics of rapamycin, several derivative compounds RAD, CCI, and AP, collectively called rapalogs have been developed.
These rapalogs have a similar ability to inhibit mTORC1 with fewer immunosuppressive effects Induction of autophagy by rapamycin or rapalogs has been tested in various model systems. Treatment of rapamycin strongly induces autophagy in yeast even in the presence of nutrients 62 ; however, the effectiveness of rapamycin on inducing autophagy in mammalian cells is dependent on the cell type.
Thus, in a panel of glioma cell lines, rapamycin effectively induces autophagy in UMG and T98G cells but is not sufficient to induce autophagy in UMG cells, although rapamycin in combination with a PI3K or AKT inhibitor sensitizes the cells to autophagy induction In addition, there are reports suggesting that rapamycin-induced autophagy may sensitize cancer cells to radiotherapy.
Treatment of PTEN -null prostate cancer cells with the rapamycin derivative RAD also called everolimus induces autophagy and sensitizes the cells to radiotherapy. Moreover, prolonging autophagy with rapamycin causes radioresistant cancer cells to enter senescence and inhibits the growth of cancer cells in a xenograft model Although further studies are necessary to determine whether the beneficial effects seen in these model systems can be attributed to increased autophagy, these studies demonstrate that rapamycin or rapalogs can induce autophagy in vitro and in vivo.
Of note, a study using a mouse model of TSC showed that autophagy is prosurvival for TSC tumorigenesis, suggesting that rapamycin or rapalog treatment is not effective, but autophagy inhibition is beneficial for the treatment of TSC Additionally, the rapalog RAD has been approved by FDA for the treatment of certain cancers such as subependymal giant cell astrocytoma, advanced hormone receptor—positive and HER2-negative breast cancer, progressive neuroendocrine tumors of pancreatic origin, and renal cell carcinoma Despite the high expectations for rapamycin and rapalogs as anticancer agents, the outcomes from clinical trials have not been uniformly positive except for certain types of cancers such as renal cell carcinoma and TSC-associated angiomyolipoma 83 , Intriguingly, one report suggests that mTORC2 activity is essential for development and survival of prostate cancer cells, but not for normal prostate epithelium Some of these inhibitors have dual inhibitory effects on mTOR and PI3K due to the similarity of their kinase domain structures The mTOR-KI torin 1 blocks the phosphorylation of all mTORC1 substrates more efficiently than does rapamycin, and as a result torin 1 elicits stronger autophagy induction in both mouse and human cell lines Interestingly, it has been shown that AZD treatment can be cytoprotective via autophagy induction in a cytotoxic chemotherapy setting Metformin is a biguanide that is widely used for the treatment of type II diabetes.
Thus, metformin treatment inhibits mTORC1-mediated protein synthesis in breast cancer cells Consequently, metformin-induced autophagy and its beneficial effects have been demonstrated in various cancer cells in vitro as well as in in vivo models — Therefore, the regulation of autophagy with mTOR inhibitors provides a new therapeutic strategy for a variety of diseases, including neurodegenerative diseases, diabetes, and cancer.
Most available mTOR inhibitors that have been rigorously tested for clinical uses are rapamycin derivatives, and the majority of these tests have been focused on their anti-proliferation effects for cancer treatment These compounds must be further evaluated in autophagy-related diseases such as neurodegeneration and cardiac myopathy, which are often associated with lysosomal and autophagy defects One critical factor that must be considered is the potential side effects of mTOR inhibitors.
It might be advantageous to use mTOR-KIs for cancer treatment but not for chronic diseases such as neurodegeneration. Therefore, in the treatment of neurodegenerative or metabolic diseases, rapalogs are probably more desirable, as they have fewer side effects. Both rapalogs and mTOR-KIs have immunosuppressive effects that could also limit their potential application.
Further pharmacokinetic studies are needed to determine the effective doses of mTOR inhibitors for inducing autophagy with minimal side effects. Autophagy induction could be beneficial or detrimental depending on the type or stage of disease For example, autophagy may promote survival during tumor initiation and development by providing nutrients to tumor cells when nutrients are limited.
Thus inhibition of autophagy may sensitize cancer cells to metabolic stress conditions, leading to cell death. Autophagy can have growth-suppressive functions, and defects in autophagy may enhance genomic instability and promote cancer development. Given the potential dual functions of autophagy in tumor suppression and promotion, more studies are needed to elucidate the precise function of autophagy in individual cancer types before a therapeutic approach can be considered.
In-depth discussions regarding the role of autophagy in tumor development and its implications in tumor therapy may be found in other articles in this Review series — For degenerative diseases, a mild induction of autophagy should protect cells from damaged proteins and organelles; thus, partial mTORC1 inhibition rather than a complete inhibition may be a possible therapeutic strategy.
We thank all members of the Guan lab for their discussion, and especially thank Steven Plouffe for critical reading of this manuscript. Go to JCI Insight. E-mail the JCI. Published January 2, - Version history.
Figure 1 The mTOR signaling network. Table 1 mTOR inhibitors and examples of their use for autophagy induction. Conflict of interest: The authors have declared that no conflict of interest exists. Reference information: J Clin Invest. Laplante M, Sabatini DM. View this article via: PubMed Google Scholar. Version 1 January 2, : No description. Sign up for email alerts.
Review Free access Phone: Find articles by Kim, Y. Find articles by Guan, K. Published January 2, - More info. Nutrients, growth factors, and cellular energy levels are key determinants of cell growth and proliferation.
Type 2 Diabetes Mellitus T2DM , a worldwide epidemics, is a progressive disease initially developing an insulin resistant state, with manifest pancreatic beta islet overwork and hyperinsulinemia. In addition, it is usually associated with other metabolic diseases such as hyperlipidemia, obesity and the metabolic syndrome. During the progression to T2DM there is a chronic activation of mTORC1 signaling pathway, which induces aging and acts as an endogenous inhibitor of autophagy. The complex 1 of mTOR mTORC1 controls cell proliferation, cell growth as well as metabolism in a variety of cell types through a complex signaling network. Autophagy is involved in the recycling of cellular components for energy generation under nutrient deprivation, and serves as a complementary degradation system to the ubiquitin-proteasome pathway. This complex is the major inhibitory node of the mechanistic target of rapamycin complex 1 mTORC1 2. In the last years, it has been determined that mTORC1 activation is produced on the lysosomal membrane through a complex mechanism involving different proteins
Arun Samidurai, Rakesh C. In the cardiovascular system, the mTOR signaling pathway integrates both intracellular and extracellular signals and serves as a central regulator of both physiological and pathological processes. MicroRNAs miRs , a class of short noncoding RNA, are an emerging intricate posttranscriptional modulator of critical gene expression for the development and maintenance of homeostasis across a wide array of tissues, including the cardiovascular system. Over the last decade, numerous studies have revealed an interplay between miRNAs and the mTOR signaling circuit in the different cardiovascular pathophysiology, like myocardial infarction, hypertrophy, fibrosis, heart failure, arrhythmia, inflammation, and atherosclerosis. In this review, we provide a comprehensive state of the current knowledge regarding the mechanisms of interactions between the mTOR signaling pathway and miRs.
Oncogenic activation of mTOR signaling induces several processes required for cancer cell growth, survival, and proliferation (Figure 3A). (A) mTOR signaling promotes tumorigenesis. Additionally, mTOR kinase inhibitors can affect cell survival and proliferation by blocking mTORC2-mediated Akt phosphorylation.
Reproduction depends on many factors, from gamete quality to placenta formation, to fetal development. The mTOR pathway is emerging as a major player that integrates several cellular processes in response to a variety of environmental cues that are relevant in many aspects of reproduction. This review provides a general overview, summarizing the involvement of the two mTOR complexes mTORC1 and mTORC2 in integrating signaling pathways, sensing environmental status, and managing physiological processes inherent to successful reproductive outcomes and pluripotent stem cell function.
The mTOR signaling pathway is a nutrient sensing mechanism coupled to mTOR, the mammalian or mechanistic target of rapamycin 15, 26, It is named after the island Rapa Nui Easter Island from whose soil it was first isolated and has broad antiproliferative and immunosuppresive properties Biochemical studies then led to the identification of the mammalian form 8, Raptor is an essential component and its genetic deletion leads to loss of TORC1 activity 3.
The mechanistic target of rapamycin mTOR ,  previously referred to as the mammalian target of rapamycin , and sometimes called FKbinding protein rapamycin-associated protein 1 FRAP1 , is a kinase that in humans is encoded by the MTOR gene. The study of TOR originated in the s with an expedition to Easter Island known by the island inhabitants as Rapa Nui , with the goal of identifying natural products from plants and soil with possible therapeutic potential.
Metrics details. Mammalian target of rapamycin mTOR regulates cell proliferation, autophagy, and apoptosis by participating in multiple signaling pathways in the body. Studies have shown that the mTOR signaling pathway is also associated with cancer, arthritis, insulin resistance, osteoporosis, and other diseases. The mTOR signaling pathway, which is often activated in tumors, not only regulates gene transcription and protein synthesis to regulate cell proliferation and immune cell differentiation but also plays an important role in tumor metabolism. Therefore, the mTOR signaling pathway is a hot target in anti-tumor therapy research. In recent years, a variety of newly discovered mTOR inhibitors have entered clinical studies, and a variety of drugs have been proven to have high activity in combination with mTOR inhibitors. The purpose of this review is to introduce the role of mTOR signaling pathway on apoptosis, autophagy, growth, and metabolism of tumor cells, and to introduce the research progress of mTOR inhibitors in the tumor field.
Mytrang H. Nixon, Kristelle J. Sabatini, Ming O.
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