109-436: 2EAK , 2EAL , 2YY1 , 2ZHK , 2ZHL , 2ZHM , 2ZHN , 3LSD , 3LSE , 3NV1 , 3NV2 , 3NV3 , 3NV4 , 3WLU , 3WV6 3965 16859 ENSG00000168961 ENSMUSG00000001123 O00182 O08573 NM_002308 NM_009587 NM_001330163 NM_001159301 NM_010708 NP_001317092 NP_002299 NP_033665 NP_001152773 NP_034838 Galectin-9 was first isolated from mouse embryonic kidney in 1997 as
218-584: A promoter sequence. The promoter is recognized and bound by transcription factors that recruit and help RNA polymerase bind to the region to initiate transcription. The recognition typically occurs as a consensus sequence like the TATA box . A gene can have more than one promoter, resulting in messenger RNAs ( mRNA ) that differ in how far they extend in the 5' end. Highly transcribed genes have "strong" promoter sequences that form strong associations with transcription factors, thereby initiating transcription at
327-875: A " start codon ", and three " stop codons " indicate the beginning and end of the protein coding region . There are 64 possible codons (four possible nucleotides at each of three positions, hence 4 possible codons) and only 20 standard amino acids; hence the code is redundant and multiple codons can specify the same amino acid. The correspondence between codons and amino acids is nearly universal among all known living organisms. MTOR 4JT6 , 1AUE , 1FAP , 1NSG , 2FAP , 2GAQ , 2NPU , 2RSE , 3FAP , 4DRH , 4DRI , 4DRJ , 4FAP , 4JSN , 4JSP , 4JSV , 4JSX , 4JT5 , 5FLC 2475 56717 ENSG00000198793 ENSMUSG00000028991 P42345 Q9JLN9 NM_004958 NM_001386500 NM_001386501 NM_020009 NP_004949 NP_064393 The mammalian target of rapamycin ( mTOR ), also referred to as
436-1093: A 36 kDa beta-galactoside lectin protein. Human galectin-9 is encoded by the LGALS9 gene . The protein has N- and C- terminal carbohydrate-binding domains connected by a link peptide. Multiple alternatively spliced transcript variants have been found for this gene. Galectin-9 is one of the most studied ligands for HAVCR2 (TIM-3) and is expressed on various tumor cells. However, it can also interact with other proteins ( CLEC7A , CD137 , CD40 ). For example, an interaction with CD40 on T-cells inhibits their proliferation and induces cell death. Galectin-9 also has important cytoplasmic, intracellular functions and controls AMPK in response to lysosomal damage that can occur upon exposure to endogenous and exogenous membrane damaging agents such as crystalline silica , cholesterol crystals , microbial toxins , proteopathic aggregates such as tau fibrils and amyloids , and signaling pathways inducing lysosomal permeabilization such as those initiated by TRAIL . Mild lysosomal damage, such as that caused by
545-445: A continuous messenger RNA , referred to as a polycistronic mRNA . The term cistron in this context is equivalent to gene. The transcription of an operon's mRNA is often controlled by a repressor that can occur in an active or inactive state depending on the presence of specific metabolites. When active, the repressor binds to a DNA sequence at the beginning of the operon, called the operator region , and represses transcription of
654-444: A core component of both complexes, mTOR functions as a serine/threonine protein kinase that regulates cell growth, cell proliferation , cell motility , cell survival, protein synthesis , autophagy , and transcription . As a core component of mTORC2, mTOR also functions as a tyrosine protein kinase that promotes the activation of insulin receptors and insulin-like growth factor 1 receptors . mTORC2 has also been implicated in
763-495: A double-helix run in opposite directions. Nucleic acid synthesis, including DNA replication and transcription occurs in the 5'→3' direction, because new nucleotides are added via a dehydration reaction that uses the exposed 3' hydroxyl as a nucleophile . The expression of genes encoded in DNA begins by transcribing the gene into RNA , a second type of nucleic acid that is very similar to DNA, but whose monomers contain
872-488: A few genes and are transferable between individuals. For example, the genes for antibiotic resistance are usually encoded on bacterial plasmids and can be passed between individual cells, even those of different species, via horizontal gene transfer . Whereas the chromosomes of prokaryotes are relatively gene-dense, those of eukaryotes often contain regions of DNA that serve no obvious function. Simple single-celled eukaryotes have relatively small amounts of such DNA, whereas
981-434: A gene - surprisingly, there is no definition that is entirely satisfactory. A gene is a DNA sequence that codes for a diffusible product. This product may be protein (as is the case in the majority of genes) or may be RNA (as is the case of genes that code for tRNA and rRNA). The crucial feature is that the product diffuses away from its site of synthesis to act elsewhere. The important parts of such definitions are: (1) that
1090-443: A gene can be found in the articles Genetics and Gene-centered view of evolution . The molecular gene definition is more commonly used across biochemistry, molecular biology, and most of genetics — the gene that is described in terms of DNA sequence. There are many different definitions of this gene — some of which are misleading or incorrect. Very early work in the field that became molecular genetics suggested
1199-565: A gene corresponds to a transcription unit; (2) that genes produce both mRNA and noncoding RNAs; and (3) regulatory sequences control gene expression but are not part of the gene itself. However, there's one other important part of the definition and it is emphasized in Kostas Kampourakis' book Making Sense of Genes . Therefore in this book I will consider genes as DNA sequences encoding information for functional products, be it proteins or RNA molecules. With 'encoding information', I mean that
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#17329062308741308-410: A gene may be split across chromosomes but those transcripts are concatenated back together into a functional sequence by trans-splicing . It is also possible for overlapping genes to share some of their DNA sequence, either on opposite strands or the same strand (in a different reading frame, or even the same reading frame). In all organisms, two steps are required to read the information encoded in
1417-404: A gene's DNA and produce the protein it specifies. First, the gene's DNA is transcribed to messenger RNA ( mRNA ). Second, that mRNA is translated to protein. RNA-coding genes must still go through the first step, but are not translated into protein. The process of producing a biologically functional molecule of either RNA or protein is called gene expression , and the resulting molecule
1526-411: A gene), DNA is first copied into RNA . RNA can be directly functional or be the intermediate template for the synthesis of a protein. The transmission of genes to an organism's offspring , is the basis of the inheritance of phenotypic traits from one generation to the next. These genes make up different DNA sequences, together called a genotype , that is specific to every given individual, within
1635-565: A gene: that of bacteriophage MS2 coat protein. The subsequent development of chain-termination DNA sequencing in 1977 by Frederick Sanger improved the efficiency of sequencing and turned it into a routine laboratory tool. An automated version of the Sanger method was used in early phases of the Human Genome Project . The theories developed in the early 20th century to integrate Mendelian genetics with Darwinian evolution are called
1744-439: A gene; however, members of a population may have different alleles at the locus, each with a slightly different gene sequence. The majority of eukaryotic genes are stored on a set of large, linear chromosomes. The chromosomes are packed within the nucleus in complex with storage proteins called histones to form a unit called a nucleosome . DNA packaged and condensed in this way is called chromatin . The manner in which DNA
1853-448: A high rate. Others genes have "weak" promoters that form weak associations with transcription factors and initiate transcription less frequently. Eukaryotic promoter regions are much more complex and difficult to identify than prokaryotic promoters. Additionally, genes can have regulatory regions many kilobases upstream or downstream of the gene that alter expression. These act by binding to transcription factors which then cause
1962-684: A kinase that negatively regulates mTOR , cooperates with Galectin-8 -based effects to inactivate mTOR downstream of the lysosomal damaging agents and conditions. The expression of galectin-9 has been detected on various hematological malignancies, such as CLL, MDS, Hodgkin's lymphomas, AML or solid tumors, such as lung cancer, breast cancer, and hepatocellular carcinoma. HAVCR2/ galectin-9 interaction attenuated T-cell expansion and effectors function in tumor microenvironment and chronic infections. Moreover, galectin-9 contributed to tumorigenesis by tumor cell transformation, cell-cycle regulation, angiogenesis, and cell adhesion. The correlative studies analyzing
2071-435: A more complex effect on mTORC2, inhibiting it only in certain cell types under prolonged exposure. Disruption of mTORC2 produces the diabetic-like symptoms of decreased glucose tolerance and insensitivity to insulin. The mTORC2 signaling pathway is less defined than the mTORC1 signaling pathway. The functions of the components of the mTORC complexes have been studied using knockdowns and knockouts and were found to produce
2180-572: A new expanded definition that includes noncoding genes. However, some modern writers still do not acknowledge noncoding genes although this so-called "new" definition has been recognised for more than half a century. Although some definitions can be more broadly applicable than others, the fundamental complexity of biology means that no definition of a gene can capture all aspects perfectly. Not all genomes are DNA (e.g. RNA viruses ), bacterial operons are multiple protein-coding regions transcribed into single large mRNAs, alternative splicing enables
2289-511: A part of the mechanism of action of the widely-prescribed anti-diabetes drug metformin . Gene In biology , the word gene has two meanings. The Mendelian gene is a basic unit of heredity . The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA . There are two types of molecular genes: protein-coding genes and non-coding genes. During gene expression (the synthesis of RNA or protein from
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#17329062308742398-404: A phosphorylation cascade activating the ribosome . Hence, the proportion of damaged proteins is enhanced. Moreover, disruption of mTORC1 directly inhibits mitochondrial respiration . These positive feedbacks on the aging process are counteracted by protective mechanisms: Decreased mTOR activity (among other factors) upregulates removal of dysfunctional cellular components via autophagy . mTOR
2507-505: A possible target of rapamycin, but suggested that the complex might interact with another element of the mechanistic cascade. In 1991, calcineurin was identified as the target of FKBP12-FK506. That of FKBP12-rapamycin remained mysterious until genetic and molecular studies in yeast established FKBP12 as the target of rapamycin, and implicated TOR1 and TOR2 as the targets of FKBP12-rapamycin in 1991 and 1993, followed by studies in 1994 when several groups, working independently, discovered
2616-400: A process known as RNA splicing . Finally, the ends of gene transcripts are defined by cleavage and polyadenylation (CPA) sites , where newly produced pre-mRNA gets cleaved and a string of ~200 adenosine monophosphates is added at the 3' end. The poly(A) tail protects mature mRNA from degradation and has other functions, affecting translation, localization, and transport of the transcript from
2725-419: A protein-coding gene consists of many elements of which the actual protein coding sequence is often only a small part. These include introns and untranslated regions of the mature mRNA. Noncoding genes can also contain introns that are removed during processing to produce the mature functional RNA. All genes are associated with regulatory sequences that are required for their expression. First, genes require
2834-413: A similar amino acid sequence to mTOR in mammals. Role of mTOR in plants The TOR kinase complex has been known for having a role in the metabolism of plants. The TORC1 complex turns on when plants are living the proper environmental conditions to survive. Once activated, plant cells undergo particular anabolic reactions. These include plant development, translation of mRNA and the growth of cells within
2943-418: A simultaneous activation via galectin-9 (which also recognizes lysosomal membrane breach) of AMPK that directly phosphorylates and activates key components ( ULK1 , Beclin 1 ) of the autophagy systems listed above and further inactivates mTORC1, allows for strong autophagy induction and autophagic removal of damaged lysosomes. Additionally, several types of ubiquitination events parallel and complement
3052-412: A single genomic region to encode multiple district products and trans-splicing concatenates mRNAs from shorter coding sequence across the genome. Since molecular definitions exclude elements such as introns, promotors, and other regulatory regions , these are instead thought of as "associated" with the gene and affect its function. An even broader operational definition is sometimes used to encompass
3161-472: A strict definition of the word "gene" with which nearly every expert can agree. First, in order for a nucleotide sequence to be considered a true gene, an open reading frame (ORF) must be present. The ORF can be thought of as the "gene itself"; it begins with a starting mark common for every gene and ends with one of three possible finish line signals. One of the key enzymes in this process, the RNA polymerase, zips along
3270-798: A substrate of mTOR, specifically of mTORC2 , upregulates expression of the glycolytic enzyme PKM2 thus contributing to the Warburg effect . mTOR is implicated in the failure of a 'pruning' mechanism of the excitatory synapses in autism spectrum disorders. mTOR signaling intersects with Alzheimer's disease (AD) pathology in several aspects, suggesting its potential role as a contributor to disease progression. In general, findings demonstrate mTOR signaling hyperactivity in AD brains. For example, postmortem studies of human AD brain reveal dysregulation in PTEN, Akt, S6K, and mTOR. mTOR signaling appears to be closely related to
3379-409: A true gene, by this definition, one has to prove that the transcript has a biological function. Early speculations on the size of a typical gene were based on high-resolution genetic mapping and on the size of proteins and RNA molecules. A length of 1500 base pairs seemed reasonable at the time (1965). This was based on the idea that the gene was the DNA that was directly responsible for production of
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3488-426: Is a central regulator of mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain, and is dysregulated in human diseases, such as diabetes , obesity , depression , and certain cancers . Rapamycin inhibits mTOR by associating with its intracellular receptor FKBP 12. The FKBP12– rapamycin complex binds directly to
3597-580: Is a key initiator of the senescence-associated secretory phenotype (SASP). Interleukin 1 alpha (IL1A) is found on the surface of senescent cells where it contributes to the production of SASP factors due to a positive feedback loop with NF-κB. Translation of mRNA for IL1A is highly dependent upon mTOR activity. mTOR activity increases levels of IL1A, mediated by MAPKAPK2 . mTOR inhibition of ZFP36L1 prevents this protein from degrading transcripts of numerous components of SASP factors. Over-activation of mTOR signaling significantly contributes to
3706-680: Is a negative regulator of autophagy in general, best studied during response to starvation, which is a metabolic response. During lysosomal damage however, mTOR inhibition activates autophagy response in its quality control function, leading to the process termed lysophagy that removes damaged lysosomes. At this stage another galectin , galectin-3 , interacts with TRIM16 to guide selective autophagy of damaged lysosomes. TRIM16 gathers ULK1 and principal components (Beclin 1 and ATG16L1 ) of other complexes (Beclin 1- VPS34 - ATG14 and ATG16L1 - ATG5 - ATG12 ) initiating autophagy , many of them being under negative control of mTOR directly such as
3815-402: Is a negative regulator of autophagy; therefore, hyperactivity in mTOR signaling should reduce Aβ clearance in the AD brain. Disruptions in autophagy may be a potential source of pathogenesis in protein misfolding diseases, including AD. Studies using mouse models of Huntington's disease demonstrate that treatment with rapamycin facilitates the clearance of huntingtin aggregates. Perhaps
3924-640: Is a phenomenon also observed in humans. Active mTORC1 is positioned on lysosomes . mTOR is inhibited when lysosomal membrane is damaged by various exogenous or endogenous agents, such as invading bacteria , membrane-permeant chemicals yielding osmotically active products (this type of injury can be modeled using membrane-permeant dipeptide precursors that polymerize in lysosomes), amyloid protein aggregates (see above section on Alzheimer's disease ) and cytoplasmic organic or inorganic inclusions including urate crystals and crystalline silica . The process of mTOR inactivation following lysosomal/endomembrane
4033-456: Is called a gene product . The nucleotide sequence of a gene's DNA specifies the amino acid sequence of a protein through the genetic code . Sets of three nucleotides, known as codons , each correspond to a specific amino acid. The principle that three sequential bases of DNA code for each amino acid was demonstrated in 1961 using frameshift mutations in the rIIB gene of bacteriophage T4 (see Crick, Brenner et al. experiment ). Additionally,
4142-493: Is deregulated in many cancers as a result of increased activity of PI3K or Akt . Similarly, overexpression of downstream mTOR effectors 4E-BP1 , S6K1 , S6K2 and eIF4E leads to poor cancer prognosis. Also, mutations in TSC proteins that inhibit the activity of mTOR may lead to a condition named tuberous sclerosis complex , which exhibits as benign lesions and increases the risk of renal cell carcinoma . Increasing mTOR activity
4251-399: Is mTOR signaling is an example of antagonistic pleiotropy , and while high mTOR signaling is good during early life, it is maintained at an inappropriately high level in old age. Calorie restriction and methionine restriction may act in part by limiting levels of essential amino acids including leucine and methionine, which are potent activators of mTOR. The administration of leucine into
4360-607: Is mediated by the protein complex termed GALTOR. At the heart of GALTOR is galectin-8 , a member of β-galactoside binding superfamily of cytosolic lectins termed galectins , which recognizes lysosomal membrane damage by binding to the exposed glycans on the lumenal side of the delimiting endomembrane. Following membrane damage, galectin-8, which normally associates with mTOR under homeostatic conditions, no longer interacts with mTOR but now instead binds to SLC38A9 , RRAGA / RRAGB , and LAMTOR1 , inhibiting Ragulator 's (LAMTOR1-5 complex) guanine nucleotide exchange function- TOR
4469-400: Is nearly the same for all known organisms. The total complement of genes in an organism or cell is known as its genome , which may be stored on one or more chromosomes . A chromosome consists of a single, very long DNA helix on which thousands of genes are encoded. The region of the chromosome at which a particular gene is located is called its locus . Each locus contains one allele of
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4578-423: Is possible that mTOR plays an important role in affecting cognitive functioning through synaptic plasticity. Further evidence for mTOR activity in neurodegeneration comes from recent findings demonstrating that eIF2α-P, an upstream target of the mTOR pathway, mediates cell death in prion diseases through sustained translational inhibition. Some evidence points to mTOR's role in reduced Aβ clearance as well. mTOR
4687-479: Is regulated by rapamycin , insulin, growth factors, phosphatidic acid , certain amino acids and their derivatives (e.g., L -leucine and β-hydroxy β-methylbutyric acid ), mechanical stimuli, and oxidative stress . mTOR Complex 2 (mTORC2) is composed of MTOR, rapamycin-insensitive companion of MTOR ( RICTOR ), MLST8 , and mammalian stress-activated protein kinase interacting protein 1 ( mSIN1 ). mTORC2 has been shown to function as an important regulator of
4796-403: Is still part of the definition of a gene in most textbooks. For example, The primary function of the genome is to produce RNA molecules. Selected portions of the DNA nucleotide sequence are copied into a corresponding RNA nucleotide sequence, which either encodes a protein (if it is an mRNA) or forms a 'structural' RNA, such as a transfer RNA (tRNA) or ribosomal RNA (rRNA) molecule. Each region of
4905-399: Is stored on the histones, as well as chemical modifications of the histone itself, regulate whether a particular region of DNA is accessible for gene expression . In addition to genes, eukaryotic chromosomes contain sequences involved in ensuring that the DNA is copied without degradation of end regions and sorted into daughter cells during cell division: replication origins , telomeres , and
5014-418: Is used as an immunosuppressant following organ transplantation. Interest in rapamycin was renewed following the discovery of the structurally related immunosuppressive natural product FK506 (later called Tacrolimus) in 1987. In 1989–90, FK506 and rapamycin were determined to inhibit T-cell receptor (TCR) and IL-2 receptor signaling pathways, respectively. The two natural products were used to discover
5123-464: The FK506- and rapamycin-binding proteins , including FKBP12 , and to provide evidence that FKBP12–FK506 and FKBP12–rapamycin might act through gain-of-function mechanisms that target distinct cellular functions. These investigations included key studies by Francis Dumont and Nolan Sigal at Merck contributing to show that FK506 and rapamycin behave as reciprocal antagonists. These studies implicated FKBP12 as
5232-573: The LC3B / GABARAP conjugation machinery through direct interactions between FIP200/RB1CC1 and ATG16L1 , (ii) ULK1 -ATG13- FIP200/RB1CC1 complex associates with the Beclin 1 - VPS34 - ATG14 via direct interactions between ATG13 's HORMA domain and ATG14 , (iii) ATG16L1 interacts with WIPI2 , which binds to PI3P , the enzymatic product of the class III PI3K Beclin 1-VPS34-ATG14. Thus, mTOR inactivation, initiated through GALTOR upon lysosomal damage, plus
5341-494: The Ragulator-Rag complex on the lysosome surface where it then becomes active in the presence of sufficient amino acids. mTOR Complex 1 (mTORC1) is composed of mTOR, regulatory-associated protein of mTOR ( Raptor ), mammalian lethal with SEC13 protein 8 ( mLST8 ) and the non-core components PRAS40 and DEPTOR . This complex functions as a nutrient/energy/redox sensor and controls protein synthesis. The activity of mTORC1
5450-535: The actin cytoskeleton through its stimulation of F- actin stress fibers, paxillin , RhoA , Rac1 , Cdc42 , and protein kinase C α ( PKCα ). mTORC2 also phosphorylates the serine/threonine protein kinase Akt/PKB on serine residue Ser473, thus affecting metabolism and survival. Phosphorylation of Akt's serine residue Ser473 by mTORC2 stimulates Akt phosphorylation on threonine residue Thr308 by PDK1 and leads to full Akt activation. In addition, mTORC2 exhibits tyrosine protein kinase activity and phosphorylates
5559-511: The aging process. The centromere is required for binding spindle fibres to separate sister chromatids into daughter cells during cell division . Prokaryotes ( bacteria and archaea ) typically store their genomes on a single, large, circular chromosome . Similarly, some eukaryotic organelles contain a remnant circular chromosome with a small number of genes. Prokaryotes sometimes supplement their chromosome with additional small circles of DNA called plasmids , which usually encode only
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#17329062308745668-401: The central dogma of molecular biology , which states that proteins are translated from RNA , which is transcribed from DNA . This dogma has since been shown to have exceptions, such as reverse transcription in retroviruses . The modern study of genetics at the level of DNA is known as molecular genetics . In 1972, Walter Fiers and his team were the first to determine the sequence of
5777-419: The centromere . Replication origins are the sequence regions where DNA replication is initiated to make two copies of the chromosome. Telomeres are long stretches of repetitive sequences that cap the ends of the linear chromosomes and prevent degradation of coding and regulatory regions during DNA replication . The length of the telomeres decreases each time the genome is replicated and has been implicated in
5886-444: The gene pool of the population of a given species . The genotype, along with environmental and developmental factors, ultimately determines the phenotype of the individual. Most biological traits occur under the combined influence of polygenes (a set of different genes) and gene–environment interactions . Some genetic traits are instantly visible, such as eye color or the number of limbs, others are not, such as blood type ,
5995-587: The insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (InsR) on the tyrosine residues Tyr1131/1136 and Tyr1146/1151, respectively, leading to full activation of IGF-IR and InsR. Rapamycin ( Sirolimus ) inhibits mTORC1, resulting in the suppression of cellular senescence . This appears to provide most of the beneficial effects of the drug (including life-span extension in animal studies). Suppression of insulin resistance by sirtuins accounts for at least some of this effect. Impaired sirtuin 3 leads to mitochondrial dysfunction . Rapamycin has
6104-543: The mechanistic target of rapamycin , and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene . mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases . mTOR links with other proteins and serves as a core component of two distinct protein complexes , mTOR complex 1 and mTOR complex 2 , which regulate different cellular processes. In particular, as
6213-549: The modern synthesis , a term introduced by Julian Huxley . This view of evolution was emphasized by George C. Williams ' gene-centric view of evolution . He proposed that the Mendelian gene is a unit of natural selection with the definition: "that which segregates and recombines with appreciable frequency." Related ideas emphasizing the centrality of Mendelian genes and the importance of natural selection in evolution were popularized by Richard Dawkins . The development of
6322-475: The neutral theory of evolution in the late 1960s led to the recognition that random genetic drift is a major player in evolution and that neutral theory should be the null hypothesis of molecular evolution. This led to the construction of phylogenetic trees and the development of the molecular clock , which is the basis of all dating techniques using DNA sequences. These techniques are not confined to molecular gene sequences but can be used on all DNA segments in
6431-750: The operon ; when the repressor is inactive transcription of the operon can occur (see e.g. Lac operon ). The products of operon genes typically have related functions and are involved in the same regulatory network . Though many genes have simple structures, as with much of biology, others can be quite complex or represent unusual edge-cases. Eukaryotic genes often have introns that are much larger than their exons, and those introns can even have other genes nested inside them . Associated enhancers may be many kilobase away, or even on entirely different chromosomes operating via physical contact between two chromosomes. A single gene can encode multiple different functional products by alternative splicing , and conversely
6540-475: The 7PA2 familial AD mutation also exhibit increased mTOR activity compared to controls, and the hyperactivity is blocked using a gamma-secretase inhibitor. These in vitro studies suggest that increasing Aβ concentrations increases mTOR signaling; however, significantly large, cytotoxic Aβ concentrations are thought to decrease mTOR signaling. Consistent with data observed in vitro, mTOR activity and activated p70S6K have been shown to be significantly increased in
6649-404: The DNA helix that produces a functional RNA molecule constitutes a gene. We define a gene as a DNA sequence that is transcribed. This definition includes genes that do not encode proteins (not all transcripts are messenger RNA). The definition normally excludes regions of the genome that control transcription but are not themselves transcribed. We will encounter some exceptions to our definition of
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#17329062308746758-450: The DNA sequence is used as a template for the production of an RNA molecule or a protein that performs some function. The emphasis on function is essential because there are stretches of DNA that produce non-functional transcripts and they do not qualify as genes. These include obvious examples such as transcribed pseudogenes as well as less obvious examples such as junk RNA produced as noise due to transcription errors. In order to qualify as
6867-766: The DNA to loop so that the regulatory sequence (and bound transcription factor) become close to the RNA polymerase binding site. For example, enhancers increase transcription by binding an activator protein which then helps to recruit the RNA polymerase to the promoter; conversely silencers bind repressor proteins and make the DNA less available for RNA polymerase. The mature messenger RNA produced from protein-coding genes contains untranslated regions at both ends which contain binding sites for ribosomes , RNA-binding proteins , miRNA , as well as terminator , and start and stop codons . In addition, most eukaryotic open reading frames contain untranslated introns , which are removed and exons , which are connected together in
6976-566: The FKBP12-Rapamycin Binding (FRB) domain of mTOR, inhibiting its activity. Plants express the mechanistic target of rapamycin (mTOR) and have a TOR kinase complex. In plants, only the TORC1 complex is present unlike that of mammalian target of rapamycin which also contains the TORC2 complex. Plant species have TOR proteins in the protein kinase and FKBP-rapamycin binding (FRB) domains that share
7085-672: The TOR1 and TOR2 genes. In 1993, Robert Cafferkey, George Livi, and colleagues, and Jeannette Kunz, Michael N. Hall , and colleagues independently cloned genes that mediate the toxicity of rapamycin in fungi, known as the TOR/DRR genes. Rapamycin arrests fungal activity at the G1 phase of the cell cycle. In mammals, it suppresses the immune system by blocking the G1 to S phase transition in T-lymphocytes . Thus, it
7194-526: The ULK1-ATG13 complex, or indirectly, such as components of t he class III PI3K (Beclin 1, ATG14 and VPS34) since they depend on activating phosphorylations by ULK1 when it is not inhibited by mTOR. These autophagy -driving components physically and functionally link up with each other integrating all processes necessary for autophagosomal formation: (i) the ULK1- ATG13 - FIP200/RB1CC1 complex associates with
7303-433: The adenines of one strand are paired with the thymines of the other strand, and so on. Due to the chemical composition of the pentose residues of the bases, DNA strands have directionality. One end of a DNA polymer contains an exposed hydroxyl group on the deoxyribose ; this is known as the 3' end of the molecule. The other end contains an exposed phosphate group; this is the 5' end . The two strands of
7412-521: The alleles. There are many different ways to use the term "gene" based on different aspects of their inheritance, selection, biological function, or molecular structure but most of these definitions fall into two categories, the Mendelian gene or the molecular gene. The Mendelian gene is the classical gene of genetics and it refers to any heritable trait. This is the gene described in The Selfish Gene . More thorough discussions of this version of
7521-578: The anti- diabetes drug metformin may contribute to the therapeutic action of metformin by activating AMPK . The mechanism of how Galectin-9 activates AMPK involves recognition of exposed lysosomal lumenal glycoproteins such as LAMP 1, LAMP2 , SCRAB2, TMEM192, etc., repulsion of deubiquitinating enzyme USP9X , increased K63 ubiquitination of TAK1 ( MAP3K7 ) kinase, which in turn phopshorylates AMPK and activates it. This signaling cascade directly links Galectin-9 intracellular function with ubiqutin systems. Galectin-9, through its regulation of AMPK,
7630-402: The complexity of these diverse phenomena, where a gene is defined as a union of genomic sequences encoding a coherent set of potentially overlapping functional products. This definition categorizes genes by their functional products (proteins or RNA) rather than their specific DNA loci, with regulatory elements classified as gene-associated regions. The existence of discrete inheritable units
7739-399: The concept that one gene makes one protein (originally 'one gene - one enzyme'). However, genes that produce repressor RNAs were proposed in the 1950s and by the 1960s, textbooks were using molecular gene definitions that included those that specified functional RNA molecules such as ribosomal RNA and tRNA (noncoding genes) as well as protein-coding genes. This idea of two kinds of genes
7848-741: The control and maintenance of the actin cytoskeleton . The study of TOR (Target Of Rapamycin) originated in the 1960s 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. In 1972, Suren Sehgal identified a small molecule, from the soil bacterium Streptomyces hygroscopicus , that he purified and initially reported to possess potent antifungal activity. He named it rapamycin , noting its original source and activity. Early testing revealed that rapamycin also had potent immunosuppressive and cytostatic anti-cancer activity. Rapamycin did not initially receive significant interest from
7957-474: The cortex and hippocampus of animal models of AD compared to controls. Pharmacologic or genetic removal of the Aβ in animal models of AD eliminates the disruption in normal mTOR activity, pointing to the direct involvement of Aβ in mTOR signaling. In addition, by injecting Aβ oligomers into the hippocampi of normal mice, mTOR hyperactivity is observed. Cognitive impairments characteristic of AD appear to be mediated by
8066-524: The distinction between a heterozygote and homozygote , and the phenomenon of discontinuous inheritance. Prior to Mendel's work, the dominant theory of heredity was one of blending inheritance , which suggested that each parent contributed fluids to the fertilization process and that the traits of the parents blended and mixed to produce the offspring. Charles Darwin developed a theory of inheritance he termed pangenesis , from Greek pan ("all, whole") and genesis ("birth") / genos ("origin"). Darwin used
8175-410: The early 1950s the prevailing view was that the genes in a chromosome acted like discrete entities arranged like beads on a string. The experiments of Benzer using mutants defective in the rII region of bacteriophage T4 (1955–1959) showed that individual genes have a simple linear structure and are likely to be equivalent to a linear section of DNA. Collectively, this body of research established
8284-436: The execution of lysophagy via autophagic receptors such as p62/ SQSTM1 , which is recruited during lysophagy, or other to be determined functions. Scleroderma , also known as systemic sclerosis , is a chronic systemic autoimmune disease characterised by hardening ( sclero ) of the skin ( derma ) that affects internal organs in its more severe forms. mTOR plays a role in fibrotic diseases and autoimmunity, and blockade of
8393-621: The expression of galectin-9 and malignant clinical features showed controversial results. This can be explained as that galectin-9 can promote tumor immune escape as well as inhibit metastasis by promoting endothelial adhesion. Therefore many factors such as tumor type, stage, and the involvement of different galectins should be take into consideration when correlating the expression level and the malignancy. Galectin-9, through its cytoplasmic action in control of AMPK, may affect various health conditions impacted by AMPK, including metabolism , obesity , diabetes , cancer , immune responses, and may be
8502-514: The fact that both protein-coding genes and noncoding genes have been known for more than 50 years, there are still a number of textbooks, websites, and scientific publications that define a gene as a DNA sequence that specifies a protein. In other words, the definition is restricted to protein-coding genes. Here is an example from a recent article in American Scientist. ... to truly assess the potential significance of de novo genes, we relied on
8611-620: The following phenotypes: Decreased TOR activity has been found to increase life span in S. cerevisiae , C. elegans , and D. melanogaster . The mTOR inhibitor rapamycin has been confirmed to increase lifespan in mice. It is hypothesized that some dietary regimes, like caloric restriction and methionine restriction, cause lifespan extension by decreasing mTOR activity. Some studies have suggested that mTOR signaling may increase during aging, at least in specific tissues like adipose tissue, and rapamycin may act in part by blocking this increase. An alternative theory
8720-413: The functional product. The discovery of introns in the 1970s meant that many eukaryotic genes were much larger than the size of the functional product would imply. Typical mammalian protein-coding genes, for example, are about 62,000 base pairs in length (transcribed region) and since there are about 20,000 of them they occupy about 35–40% of the mammalian genome (including the human genome). In spite of
8829-529: The galectin-driven processes: Ubiquitination of TRIM16-ULK1-Beclin-1 stabilizes these complexes to promote autophagy activation as described above. ATG16L1 has an intrinsic binding affinity for ubiquitin ); whereas ubiquitination by a glycoprotein-specific FBXO27-endowed ubiquitin ligase of several damage-exposed glycosylated lysosomal membrane proteins such as LAMP1 , LAMP2 , GNS/ N-acetylglucosamine-6-sulfatase , TSPAN6/ tetraspanin-6 , PSAP/ prosaposin , and TMEM192/transmembrane protein 192 may contribute to
8938-421: The genome. The vast majority of organisms encode their genes in long strands of DNA (deoxyribonucleic acid). DNA consists of a chain made from four types of nucleotide subunits, each composed of: a five-carbon sugar ( 2-deoxyribose ), a phosphate group, and one of the four bases adenine , cytosine , guanine , and thymine . Two chains of DNA twist around each other to form a DNA double helix with
9047-421: The genomes of complex multicellular organisms , including humans, contain an absolute majority of DNA without an identified function. This DNA has often been referred to as " junk DNA ". However, more recent analyses suggest that, although protein-coding DNA makes up barely 2% of the human genome , about 80% of the bases in the genome may be expressed, so the term "junk DNA" may be a misnomer. The structure of
9156-470: The initiation and development of tumors and mTOR activity was found to be deregulated in many types of cancer including breast, prostate, lung, melanoma, bladder, brain, and renal carcinomas. Reasons for constitutive activation are several. Among the most common are mutations in tumor suppressor PTEN gene. PTEN phosphatase negatively affects mTOR signalling through interfering with the effect of PI3K , an upstream effector of mTOR. Additionally, mTOR activity
9265-416: The loss of muscle mass and strength during muscle wasting in old age, cancer cachexia , and muscle atrophy from physical inactivity . mTORC2 activation appears to mediate neurite outgrowth in differentiated mouse neuro2a cells . Intermittent mTOR activation in prefrontal neurons by β-hydroxy β-methylbutyrate inhibits age-related cognitive decline associated with dendritic pruning in animals, which
9374-628: The mTOR kinase as its direct target in mammalian tissues. Sequence analysis of mTOR revealed it to be the direct ortholog of proteins encoded by the yeast target of rapamycin 1 and 2 (TOR1 and TOR2 ) genes, which Joseph Heitman, Rao Movva, and Michael N. Hall had identified in August 1991 and May 1993. Independently, George Livi and colleagues later reported the same genes, which they called dominant rapamycin resistance 1 and 2 (DRR1 and DRR2) , in studies published in October 1993. The protein, now called mTOR,
9483-639: The meaning of the "m" was later changed to "mechanistic". Similarly, with subsequent discoveries the zebra fish TOR was named zTOR, the Arabidopsis thaliana TOR was named AtTOR, and the Drosophila TOR was named dTOR. In 2009 the FRAP1 gene name was officially changed by the HUGO Gene Nomenclature Committee (HGNC) to mTOR, which stands for mechanistic target of rapamycin. The discovery of TOR and
9592-409: The natural product rapamycin by Joseph Heitman , Rao Movva, and Michael N. Hall in 1991; by David M. Sabatini , Hediye Erdjument-Bromage, Mary Lui, Paul Tempst, and Solomon H. Snyder in 1994; and by Candace J. Sabers, Mary M. Martin, Gregory J. Brunn, Josie M. Williams, Francis J. Dumont, Gregory Wiederrecht, and Robert T. Abraham in 1995. In 1991, working in yeast, Hall and colleagues identified
9701-413: The nucleus. Splicing, followed by CPA, generate the final mature mRNA , which encodes the protein or RNA product. Many noncoding genes in eukaryotes have different transcription termination mechanisms and they do not have poly(A) tails. Many prokaryotic genes are organized into operons , with multiple protein-coding sequences that are transcribed as a unit. The genes in an operon are transcribed as
9810-405: The pharmaceutical industry until the 1980s, when Wyeth-Ayerst supported Sehgal's efforts to further investigate rapamycin's effect on the immune system. This eventually led to its FDA approval as an immunosuppressant following kidney transplantation. However, prior to its FDA approval, how rapamycin worked remained completely unknown. The discovery of TOR and mTOR stemmed from independent studies of
9919-431: The phosphate–sugar backbone spiralling around the outside, and the bases pointing inward with adenine base pairing to thymine and guanine to cytosine. The specificity of base pairing occurs because adenine and thymine align to form two hydrogen bonds , whereas cytosine and guanine form three hydrogen bonds. The two strands in a double helix must, therefore, be complementary , with their sequence of bases matching such that
10028-638: The phosphorylation of PRAS-40, which detaches from and allows for the mTOR hyperactivity when it is phosphorylated; inhibiting PRAS-40 phosphorylation prevents Aβ-induced mTOR hyperactivity. Given these findings, the mTOR signaling pathway appears to be one mechanism of Aβ-induced toxicity in AD. The hyperphosphorylation of tau proteins into neurofibrillary tangles is one hallmark of AD. p70S6K activation has been shown to promote tangle formation as well as mTOR hyperactivity through increased phosphorylation and reduced dephosphorylation. It has also been proposed that mTOR contributes to tau pathology by increasing
10137-619: The plant. However, the TORC1 complex activation stops catabolic processes such as autophagy from occurring. TOR kinase signaling in plants has been found to aid in senescence, flowering, root and leaf growth, embryogenesis, and the meristem activation above the root cap of a plant. mTOR is also found to be highly involved in developing embryo tissue in plants. mTOR is the catalytic subunit of two structurally distinct complexes: mTORC1 and mTORC2. The two complexes localize to different subcellular compartments, thus affecting their activation and function. Upon activation by Rheb, mTORC1 localizes to
10246-571: The presence of soluble amyloid beta (Aβ) and tau proteins, which aggregate and form two hallmarks of the disease, Aβ plaques and neurofibrillary tangles, respectively. In vitro studies have shown Aβ to be an activator of the PI3K/AKT pathway , which in turn activates mTOR. In addition, applying Aβ to N2K cells increases the expression of p70S6K, a downstream target of mTOR known to have higher expression in neurons that eventually develop neurofibrillary tangles. Chinese hamster ovary cells transfected with
10355-422: The rat brain has been shown to decrease food intake and body weight via activation of the mTOR pathway in the hypothalamus . According to the free radical theory of aging , reactive oxygen species cause damage to mitochondrial proteins and decrease ATP production. Subsequently, via ATP sensitive AMPK , the mTOR pathway is inhibited and ATP-consuming protein synthesis is downregulated, since mTORC1 initiates
10464-431: The risk for specific diseases, or the thousands of basic biochemical processes that constitute life . A gene can acquire mutations in its sequence , leading to different variants, known as alleles , in the population . These alleles encode slightly different versions of a gene, which may cause different phenotypical traits. Genes evolve due to natural selection or survival of the fittest and genetic drift of
10573-609: The same treatment may be useful in clearing Aβ deposits as well. Hyperactive mTOR pathways have been identified in certain lymphoproliferative diseases such as autoimmune lymphoproliferative syndrome (ALPS), multicentric Castleman disease , and post-transplant lymphoproliferative disorder (PTLD). mTORC1 activation is required for myofibrillar muscle protein synthesis and skeletal muscle hypertrophy in humans in response to both physical exercise and ingestion of certain amino acids or amino acid derivatives. Persistent inactivation of mTORC1 signaling in skeletal muscle facilitates
10682-467: The strand of DNA like a train on a monorail, transcribing it into its messenger RNA form. This point brings us to our second important criterion: A true gene is one that is both transcribed and translated. That is, a true gene is first used as a template to make transient messenger RNA, which is then translated into a protein. This restricted definition is so common that it has spawned many recent articles that criticize this "standard definition" and call for
10791-485: The subsequent identification of mTOR opened the door to the molecular and physiological study of what is now called the mTOR pathway and had a catalytic effect on the growth of the field of chemical biology, where small molecules are used as probes of biology. mTOR integrates the input from upstream pathways , including insulin , growth factors (such as IGF-1 and IGF-2 ), and amino acids . mTOR also senses cellular nutrient, oxygen, and energy levels. The mTOR pathway
10900-461: The sugar ribose rather than deoxyribose . RNA also contains the base uracil in place of thymine . RNA molecules are less stable than DNA and are typically single-stranded. Genes that encode proteins are composed of a series of three- nucleotide sequences called codons , which serve as the "words" in the genetic "language". The genetic code specifies the correspondence during protein translation between codons and amino acids . The genetic code
11009-805: The term gemmule to describe hypothetical particles that would mix during reproduction. Mendel's work went largely unnoticed after its first publication in 1866, but was rediscovered in the late 19th century by Hugo de Vries , Carl Correns , and Erich von Tschermak , who (claimed to have) reached similar conclusions in their own research. Specifically, in 1889, Hugo de Vries published his book Intracellular Pangenesis , in which he postulated that different characters have individual hereditary carriers and that inheritance of specific traits in organisms comes in particles. De Vries called these units "pangenes" ( Pangens in German), after Darwin's 1868 pangenesis theory. Twenty years later, in 1909, Wilhelm Johannsen introduced
11118-436: The term gene , he explained his results in terms of discrete inherited units that give rise to observable physical characteristics. This description prefigured Wilhelm Johannsen 's distinction between genotype (the genetic material of an organism) and phenotype (the observable traits of that organism). Mendel was also the first to demonstrate independent assortment , the distinction between dominant and recessive traits,
11227-412: The term "gene" (inspired by the ancient Greek : γόνος, gonos , meaning offspring and procreation) and, in 1906, William Bateson , that of " genetics " while Eduard Strasburger , among others, still used the term "pangene" for the fundamental physical and functional unit of heredity. Advances in understanding genes and inheritance continued throughout the 20th century. Deoxyribonucleic acid (DNA)
11336-551: The translation of tau and other proteins. Synaptic plasticity is a key contributor to learning and memory, two processes that are severely impaired in AD patients. Translational control, or the maintenance of protein homeostasis, has been shown to be essential for neural plasticity and is regulated by mTOR. Both protein over- and under-production via mTOR activity seem to contribute to impaired learning and memory. Furthermore, given that deficits resulting from mTOR overactivity can be alleviated through treatment with rapamycin, it
11445-446: Was first suggested by Gregor Mendel (1822–1884). From 1857 to 1864, in Brno , Austrian Empire (today's Czech Republic), he studied inheritance patterns in 8000 common edible pea plants , tracking distinct traits from parent to offspring. He described these mathematically as 2 combinations where n is the number of differing characteristics in the original peas. Although he did not use
11554-662: Was named TOR, the Target of Rapamycin, by Joe Heitman, Rao Movva, and Mike Hall. TOR was originally discovered at the Biozentrum and Sandoz Pharmaceuticals in 1991 in Basel, Switzerland, and the name TOR pays further homage to this discovery, as TOR means doorway or gate in German, and the city of Basel was once ringed by a wall punctuated with gates into the city, including the iconic Spalentor . "mTOR" initially meant "mammalian target of rapamycin", but
11663-455: Was originally named FRAP by Stuart L. Schreiber and RAFT1 by David M. Sabatini; FRAP1 was used as its official gene symbol in humans. Because of these different names, mTOR, which had been first used by Robert T. Abraham, was increasingly adopted by the community of scientists working on the mTOR pathway to refer to the protein and in homage to the original discovery of the TOR protein in yeast that
11772-430: Was shown to be the molecular repository of genetic information by experiments in the 1940s to 1950s. The structure of DNA was studied by Rosalind Franklin and Maurice Wilkins using X-ray crystallography , which led James D. Watson and Francis Crick to publish a model of the double-stranded DNA molecule whose paired nucleotide bases indicated a compelling hypothesis for the mechanism of genetic replication. In
11881-528: Was shown to drive cell cycle progression and increase cell proliferation mainly due to its effect on protein synthesis. Moreover, active mTOR supports tumor growth also indirectly by inhibiting autophagy . Constitutively activated mTOR functions in supplying carcinoma cells with oxygen and nutrients by increasing the translation of HIF1A and supporting angiogenesis . mTOR also aids in another metabolic adaptation of cancerous cells to support their increased growth rate—activation of glycolytic metabolism . Akt2 ,
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