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61-442: 7048 21813 ENSG00000163513 ENSMUSG00000032440 P37173 Q62312 NM_001024847 NM_003242 NM_009371 NM_029575 NP_001020018 NP_003233 NP_033397 NP_083851 Transforming growth factor, beta receptor II ( 70/80kDa ) is a TGF beta receptor . TGFBR2 is its human gene . It is a tumor suppressor gene . This gene encodes a member of the serine/threonine protein kinase family and

122-455: A phenotype . These products are often proteins , but in non-protein-coding genes such as transfer RNA (tRNA) and small nuclear RNA (snRNA) , the product is a functional non-coding RNA . The process of gene expression is used by all known life— eukaryotes (including multicellular organisms ), prokaryotes ( bacteria and archaea ), and utilized by viruses —to generate the macromolecular machinery for life. In genetics , gene expression

183-413: A 5′ untranslated region (5′UTR), a protein-coding region or open reading frame (ORF), and a 3′ untranslated region (3′UTR). The coding region carries information for protein synthesis encoded by the genetic code to form triplets. Each triplet of nucleotides of the coding region is called a codon and corresponds to a binding site complementary to an anticodon triplet in transfer RNA. Transfer RNAs with

244-669: A compact fold containing nine beta-strands and a single helix stabilised by a network of six intra strand disulphide bonds . The folding topology includes a central five-stranded antiparallel beta-sheet, eight-residues long at its centre, covered by a second layer consisting of two segments of two-stranded antiparallel beta-sheets (beta1-beta4, beta3-beta9). TGF beta receptor Transforming growth factor beta (TGFβ) receptors are single pass serine/threonine kinase receptors that belong to TGFβ receptor family . They exist in several different isoforms that can be homo - or heterodimeric . The number of characterized ligands in

305-692: A control factor with the gene), modulation interaction of a control factor with the transcription machinery and epigenetic (non-sequence changes in DNA structure that influence transcription). Direct interaction with DNA is the simplest and the most direct method by which a protein changes transcription levels. Genes often have several protein binding sites around the coding region with the specific function of regulating transcription. There are many classes of regulatory DNA binding sites known as enhancers , insulators and silencers . The mechanisms for regulating transcription are varied, from blocking key binding sites on

366-400: A gene coding for a protein is only possible if the messenger RNA carrying the code survives long enough to be translated. In a typical cell, an RNA molecule is only stable if specifically protected from degradation. RNA degradation has particular importance in regulation of expression in eukaryotic cells where mRNA has to travel significant distances before being translated. In eukaryotes, RNA

427-541: A gene promoter by TET enzyme activity increases transcription of the gene. In a rat, contextual fear conditioning (CFC) is a painful learning experience. Just one episode of CFC can result in a life-long fearful memory. After an episode of CFC, cytosine methylation is altered in the promoter regions of about 9.17% of all genes in the hippocampus neuron DNA of a rat. The hippocampus is where new memories are initially stored. After CFC about 500 genes have increased transcription (often due to demethylation of CpG sites in

488-727: A gene's promoter CpG sites are methylated the gene becomes silenced. Colorectal cancers typically have 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, transcriptional silencing may be of more importance than mutation in causing progression to cancer. For example, in colorectal cancers about 600 to 800 genes are transcriptionally silenced by CpG island methylation (see regulation of transcription in cancer ). Transcriptional repression in cancer can also occur by other epigenetic mechanisms, such as altered expression of microRNAs . In breast cancer, transcriptional repression of BRCA1 may occur more frequently by over-transcribed microRNA-182 than by hypermethylation of

549-431: A group of small Cajal body-specific RNAs (scaRNAs) , which are structurally similar to snoRNAs. In eukaryotes most mature RNA must be exported to the cytoplasm from the nucleus . While some RNAs function in the nucleus, many RNAs are transported through the nuclear pores and into the cytosol . Export of RNAs requires association with specific proteins known as exportins. Specific exportin molecules are responsible for

610-499: A high affinity for both homodimeric TGFβ1 and TGFβ2 and in addition the heterodimer TGF-β1.2. The TGFβ receptors also bind TGFβ3 . This article about a biochemical receptor is a stub . You can help Misplaced Pages by expanding it . Gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA , and ultimately affect

671-487: A newly synthesized RNA molecule. The nuclear membrane in eukaryotes allows further regulation of transcription factors by the duration of their presence in the nucleus, which is regulated by reversible changes in their structure and by binding of other proteins. Environmental stimuli or endocrine signals may cause modification of regulatory proteins eliciting cascades of intracellular signals, which result in regulation of gene expression. It has become apparent that there

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732-531: A promoter by a DNA loop, govern transcription level of the target gene. Mediator (a complex usually consisting of about 26 proteins in an interacting structure) communicates regulatory signals from enhancer DNA-bound transcription factors directly to the RNA polymerase II (pol II) enzyme bound to the promoter. Enhancers, when active, are generally transcribed from both strands of DNA with RNA polymerases acting in two different directions, producing two eRNAs as illustrated in

793-432: A promoter region) and about 1,000 genes have decreased transcription (often due to newly formed 5-methylcytosine at CpG sites in a promoter region). The pattern of induced and repressed genes within neurons appears to provide a molecular basis for forming the first transient memory of this training event in the hippocampus of the rat brain. Some specific mechanisms guiding new DNA methylations and new DNA demethylations in

854-425: A sequence of mRNA into a linear chain of amino acids . This polypeptide lacks any developed three-dimensional structure (the left hand side of the neighboring figure). The polypeptide then folds into its characteristic and functional three-dimensional structure from a random coil . Amino acids interact with each other to produce a well-defined three-dimensional structure, the folded protein (the right hand side of

915-420: A single gene. Because these transcripts can be potentially translated into different proteins, splicing extends the complexity of eukaryotic gene expression and the size of a species proteome . Extensive RNA processing may be an evolutionary advantage made possible by the nucleus of eukaryotes. In prokaryotes, transcription and translation happen together, whilst in eukaryotes, the nuclear membrane separates

976-449: A splice-isoform of DNA methyltransferase DNMT3A, which adds methyl groups to cytosines in DNA. This isoform is induced by synaptic activity, and its location of action appears to be determined by histone post-translational modifications (a histone code ). The resulting new messenger RNAs are then transported by messenger RNP particles (neuronal granules) to synapses of the neurons, where they can be translated into proteins affecting

1037-418: Is a significant influence of non-DNA-sequence specific effects on transcription. These effects are referred to as epigenetic and involve the higher order structure of DNA, non-sequence specific DNA binding proteins and chemical modification of DNA. In general epigenetic effects alter the accessibility of DNA to proteins and so modulate transcription. In eukaryotes the structure of chromatin , controlled by

1098-404: Is a widespread mechanism for epigenetic influence on gene expression and is seen in bacteria and eukaryotes and has roles in heritable transcription silencing and transcription regulation. Methylation most often occurs on a cytosine (see Figure). Methylation of cytosine primarily occurs in dinucleotide sequences where a cytosine is followed by a guanine, a CpG site . The number of CpG sites in

1159-497: Is bound by multiple poly(A)-binding proteins (PABPs) necessary for mRNA export and translation re-initiation. In the inverse process of deadenylation, poly(A) tails are shortened by the CCR4-Not 3′-5′ exonuclease, which often leads to full transcript decay. A very important modification of eukaryotic pre-mRNA is RNA splicing . The majority of eukaryotic pre-mRNAs consist of alternating segments called exons and introns . During

1220-463: Is one of the main roles of the endoplasmic reticulum in eukaryotes. Secretory proteins of eukaryotes or prokaryotes must be translocated to enter the secretory pathway. Newly synthesized proteins are directed to the eukaryotic Sec61 or prokaryotic SecYEG translocation channel by signal peptides . The efficiency of protein secretion in eukaryotes is very dependent on the signal peptide which has been used. Many proteins are destined for other parts of

1281-627: Is performed in the nucleus by three types of RNA polymerases, each of which needs a special DNA sequence called the promoter and a set of DNA-binding proteins— transcription factors —to initiate the process (see regulation of transcription below). RNA polymerase I is responsible for transcription of ribosomal RNA (rRNA) genes. RNA polymerase II (Pol II) transcribes all protein-coding genes but also some non-coding RNAs ( e.g. , snRNAs, snoRNAs or long non-coding RNAs ). RNA polymerase III transcribes 5S rRNA , transfer RNA (tRNA) genes, and some small non-coding RNAs ( e.g. , 7SK ). Transcription ends when

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1342-782: Is stabilised by certain post-transcriptional modifications, particularly the 5′ cap and poly-adenylated tail . Intentional degradation of mRNA is used not just as a defence mechanism from foreign RNA (normally from viruses) but also as a route of mRNA destabilisation . If an mRNA molecule has a complementary sequence to a small interfering RNA then it is targeted for destruction via the RNA interference pathway. Three prime untranslated regions (3′UTRs) of messenger RNAs (mRNAs) often contain regulatory sequences that post-transcriptionally influence gene expression. Such 3′-UTRs often contain both binding sites for microRNAs (miRNAs) as well as for regulatory proteins. By binding to specific sites within

1403-425: Is the basis for cellular differentiation , development , morphogenesis and the versatility and adaptability of any organism . Gene regulation may therefore serve as a substrate for evolutionary change. The production of a RNA copy from a DNA strand is called transcription , and is performed by RNA polymerases , which add one ribonucleotide at a time to a growing RNA strand as per the complementarity law of

1464-496: Is the most fundamental level at which the genotype gives rise to the phenotype , i.e. observable trait. The genetic information stored in DNA represents the genotype, whereas the phenotype results from the "interpretation" of that information. Such phenotypes are often displayed by the synthesis of proteins that control the organism's structure and development, or that act as enzymes catalyzing specific metabolic pathways. All steps in

1525-590: Is then processed to mature miRNAs in the cytoplasm by interaction with the endonuclease Dicer , which also initiates the formation of the RNA-induced silencing complex (RISC) , composed of the Argonaute protein. Even snRNAs and snoRNAs themselves undergo series of modification before they become part of functional RNP complex. This is done either in the nucleoplasm or in the specialized compartments called Cajal bodies . Their bases are methylated or pseudouridinilated by

1586-548: The hippocampus during memory establishment have been established (see for summary). One mechanism includes guiding the short isoform of the TET1 DNA demethylation enzyme, TET1s, to about 600 locations on the genome. The guidance is performed by association of TET1s with EGR1 protein, a transcription factor important in memory formation. Bringing TET1s to these locations initiates DNA demethylation at those sites, up-regulating associated genes. A second mechanism involves DNMT3A2,

1647-500: The histone code , regulates access to DNA with significant impacts on the expression of genes in euchromatin and heterochromatin areas. Gene expression in mammals is regulated by many cis-regulatory elements , including core promoters and promoter-proximal elements that are located near the transcription start sites of genes, upstream on the DNA (towards the 5' region of the sense strand ). Other important cis-regulatory modules are localized in DNA regions that are distant from

1708-411: The 3′ end is removed by the tRNase Z enzyme and the non-templated 3′ CCA tail is added by a nucleotidyl transferase . In the case of micro RNA (miRNA) , miRNAs are first transcribed as primary transcripts or pri-miRNA with a cap and poly-A tail and processed to short, 70-nucleotide stem-loop structures known as pre-miRNA in the cell nucleus by the enzymes Drosha and Pasha . After being exported, it

1769-444: The 3′-UTR, miRNAs can decrease gene expression of various mRNAs by either inhibiting translation or directly causing degradation of the transcript. The 3′-UTR also may have silencer regions that bind repressor proteins that inhibit the expression of a mRNA. The 3′-UTR often contains microRNA response elements (MREs) . MREs are sequences to which miRNAs bind. These are prevalent motifs within 3′-UTRs. Among all regulatory motifs within

1830-454: The BRCA1 promoter (see Low expression of BRCA1 in breast and ovarian cancers ). In eukaryotes, where export of RNA is required before translation is possible, nuclear export is thought to provide additional control over gene expression. All transport in and out of the nucleus is via the nuclear pore and transport is controlled by a wide range of importin and exportin proteins. Expression of

1891-481: The DNA for RNA polymerase to acting as an activator and promoting transcription by assisting RNA polymerase binding. The activity of transcription factors is further modulated by intracellular signals causing protein post-translational modification including phosphorylation , acetylation , or glycosylation . These changes influence a transcription factor's ability to bind, directly or indirectly, to promoter DNA, to recruit RNA polymerase, or to favor elongation of

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1952-400: The RNA from decapping . Another modification is 3′ cleavage and polyadenylation . They occur if polyadenylation signal sequence (5′- AAUAAA-3′) is present in pre-mRNA, which is usually between protein-coding sequence and terminator. The pre-mRNA is first cleaved and then a series of ~200 adenines (A) are added to form poly(A) tail, which protects the RNA from degradation. The poly(A) tail

2013-420: The RNA. For some non-coding RNA, the mature RNA is the final gene product. In the case of messenger RNA (mRNA) the RNA is an information carrier coding for the synthesis of one or more proteins. mRNA carrying a single protein sequence (common in eukaryotes) is monocistronic whilst mRNA carrying multiple protein sequences (common in prokaryotes) is known as polycistronic . Every mRNA consists of three parts:

2074-545: The TGFB receptor subfamily. The encoded protein is a transmembrane protein that has a protein kinase domain, forms a heterodimeric complex with another receptor protein, and binds TGF-beta. This receptor/ligand complex phosphorylates proteins, which then enter the nucleus and regulate the transcription of a subset of genes related to cell proliferation. Mutations in this gene have been associated with Marfan syndrome , Loeys-Deitz aortic aneurysm syndrome , Osler–Weber–Rendu syndrome , and

2135-684: The TGFβ superfamily far exceeds the number of known receptors, suggesting the promiscuity that exists between the ligand and receptor interactions. TGFβ is a growth factor and cytokine involved in paracrine signalling and can be found in many different tissue types, including brain , heart , kidney , liver , bone , and testes . Over- expression of TGFβ can induce renal fibrosis , causing kidney disease , as well as diabetes , and ultimately end-stage renal disease . Recent developments have found that, using certain types of protein antagonists against TGFβ receptors, can halt and in some cases reverse

2196-417: The accumulation of misfolded proteins. Many allergies are caused by the folding of the proteins, for the immune system does not produce antibodies for certain protein structures. Enzymes called chaperones assist the newly formed protein to attain ( fold into) the 3-dimensional structure it needs to function. Similarly, RNA chaperones help RNAs attain their functional shapes. Assisting protein folding

2257-410: The activities of synapses. In particular, the brain-derived neurotrophic factor gene ( BDNF ) is known as a "learning gene". After CFC there was upregulation of BDNF gene expression, related to decreased CpG methylation of certain internal promoters of the gene, and this was correlated with learning. The majority of gene promoters contain a CpG island with numerous CpG sites . When many of

2318-454: The cell and many are exported, for example, digestive enzymes , hormones and extracellular matrix proteins. In eukaryotes the export pathway is well developed and the main mechanism for the export of these proteins is translocation to the endoplasmic reticulum, followed by transport via the Golgi apparatus . Regulation of gene expression is the control of the amount and timing of appearance of

2379-474: The cell or insertion into a cell membrane . Proteins that are supposed to be produced at the endoplasmic reticulum are recognised part-way through the translation process. This is governed by the signal recognition particle —a protein that binds to the ribosome and directs it to the endoplasmic reticulum when it finds a signal peptide on the growing (nascent) amino acid chain. Each protein exists as an unfolded polypeptide or random coil when translated from

2440-423: The cell than the cytosol and a wide range of signalling sequences or (signal peptides) are used to direct proteins to where they are supposed to be. In prokaryotes this is normally a simple process due to limited compartmentalisation of the cell. However, in eukaryotes there is a great variety of different targeting processes to ensure the protein arrives at the correct organelle. Not all proteins remain within

2501-400: The development of various types of tumors. At least 73 disease-causing mutations in this gene have been discovered. Alternatively spliced transcript variants encoding different isoforms have been characterized. TGF beta receptor 2 has been shown to interact with: TGF beta receptor 2 consists of a C-terminal protein kinase domain and an N-terminal ectodomain. The ectodomain consists of

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2562-439: The dimer is anchored to its binding motif on the enhancer and the other member is anchored to its binding motif on the promoter (represented by the red zigzags in the illustration). Several cell function-specific transcription factors (among the about 1,600 transcription factors in a human cell) generally bind to specific motifs on an enhancer. A small combination of these enhancer-bound transcription factors, when brought close to

2623-419: The effects of renal fibrosis. Three TGFβ superfamily receptors specific for TGFβ, the TGFβ receptors, can be distinguished by their structural and functional properties. TGFβR1 (ALK5) and TGFβR2 have similar ligand-binding affinities and can be distinguished from each other only by peptide mapping . Both TGFβR1 and TGFβR2 have a high affinity for TGFβ1 and low affinity for TGFβ2 . TGFβR3 (β-glycan) has

2684-423: The export of a given RNA type. mRNA transport also requires the correct association with Exon Junction Complex (EJC), which ensures that correct processing of the mRNA is completed before export. In some cases RNAs are additionally transported to a specific part of the cytoplasm, such as a synapse ; they are then towed by motor proteins that bind through linker proteins to specific sequences (called "zipcodes") on

2745-485: The figure) known as the native state . The resulting three-dimensional structure is determined by the amino acid sequence ( Anfinsen's dogma ). The correct three-dimensional structure is essential to function, although some parts of functional proteins may remain unfolded . Failure to fold into the intended shape usually produces inactive proteins with different properties including toxic prions . Several neurodegenerative and other diseases are believed to result from

2806-494: The figure. An inactive enhancer may be bound by an inactive transcription factor. Phosphorylation of the transcription factor may activate it and that activated transcription factor may then activate the enhancer to which it is bound (see small red star representing phosphorylation of transcription factor bound to enhancer in the illustration). An activated enhancer begins transcription of its RNA before activating transcription of messenger RNA from its target gene. DNA methylation

2867-430: The functional product of a gene. Control of expression is vital to allow a cell to produce the gene products it needs when it needs them; in turn, this gives cells the flexibility to adapt to a variable environment, external signals, damage to the cell, and other stimuli. More generally, gene regulation gives the cell control over all structure and function, and is the basis for cellular differentiation , morphogenesis and

2928-417: The gene expression process may be modulated (regulated), including the transcription , RNA splicing , translation , and post-translational modification of a protein. Regulation of gene expression gives control over the timing, location, and amount of a given gene product (protein or ncRNA) present in a cell and can have a profound effect on the cellular structure and function. Regulation of gene expression

2989-438: The gene—an unstable product results in a low expression level. In general gene expression is regulated through changes in the number and type of interactions between molecules that collectively influence transcription of DNA and translation of RNA. Some simple examples of where gene expression is important are: Regulation of transcription can be broken down into three main routes of influence; genetic (direct interaction of

3050-513: The human genome is about 28 million. Depending on the type of cell, about 70% of the CpG sites have a methylated cytosine. Methylation of cytosine in DNA has a major role in regulating gene expression. Methylation of CpGs in a promoter region of a gene usually represses gene transcription while methylation of CpGs in the body of a gene increases expression. TET enzymes play a central role in demethylation of methylated cytosines. Demethylation of CpGs in

3111-437: The nucleotide bases. This RNA is complementary to the template 3′ → 5′ DNA strand, with the exception that thymines (T) are replaced with uracils (U) in the RNA and possible errors. In bacteria, transcription is carried out by a single type of RNA polymerase, which needs to bind a DNA sequence called a Pribnow box with the help of the sigma factor protein (σ factor) to start transcription. In eukaryotes, transcription

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3172-416: The point of transcription (co-transcriptionally), often using a messenger RNA that is still in the process of being created. In eukaryotes translation can occur in a variety of regions of the cell depending on where the protein being written is supposed to be. Major locations are the cytoplasm for soluble cytoplasmic proteins and the membrane of the endoplasmic reticulum for proteins that are for export from

3233-529: The polymerase encounters a sequence called the terminator . While transcription of prokaryotic protein-coding genes creates messenger RNA (mRNA) that is ready for translation into protein, transcription of eukaryotic genes leaves a primary transcript of RNA (pre-RNA), which first has to undergo a series of modifications to become a mature RNA. Types and steps involved in the maturation processes vary between coding and non-coding preRNAs; i.e. even though preRNA molecules for both mRNA and tRNA undergo splicing,

3294-428: The process of splicing, an RNA-protein catalytical complex known as spliceosome catalyzes two transesterification reactions, which remove an intron and release it in form of lariat structure, and then splice neighbouring exons together. In certain cases, some introns or exons can be either removed or retained in mature mRNA. This so-called alternative splicing creates series of different transcripts originating from

3355-456: The promoters of their target genes. Multiple enhancers, each often tens or hundred of thousands of nucleotides distant from their target genes, loop to their target gene promoters and coordinate with each other to control gene expression. The illustration shows an enhancer looping around to come into proximity with the promoter of a target gene. The loop is stabilized by a dimer of a connector protein (e.g. dimer of CTCF or YY1 ). One member of

3416-483: The same anticodon sequence always carry an identical type of amino acid . Amino acids are then chained together by the ribosome according to the order of triplets in the coding region. The ribosome helps transfer RNA to bind to messenger RNA and takes the amino acid from each transfer RNA and makes a structure-less protein out of it. Each mRNA molecule is translated into many protein molecules, on average ~2800 in mammals. In prokaryotes translation generally occurs at

3477-473: The steps and machinery involved are different. The processing of non-coding RNA is described below (non-coding RNA maturation). The processing of pre-mRNA include 5′ capping , which is set of enzymatic reactions that add 7-methylguanosine (m G) to the 5′ end of pre-mRNA and thus protect the RNA from degradation by exonucleases . The m G cap is then bound by cap binding complex heterodimer (CBP20/CBP80), which aids in mRNA export to cytoplasm and also protect

3538-428: The target RNA and thus position the modification at a precise site, the protein part performs the catalytical reaction. In eukaryotes, in particular a snoRNP called RNase, MRP cleaves the 45S pre-rRNA into the 28S , 5.8S , and 18S rRNAs . The rRNA and RNA processing factors form large aggregates called the nucleolus . In the case of transfer RNA (tRNA), for example, the 5′ sequence is removed by RNase P , whereas

3599-419: The transcription start sites. These include enhancers , silencers , insulators and tethering elements. Enhancers and their associated transcription factors have a leading role in the regulation of gene expression. Enhancers are genome regions that regulate genes. Enhancers control cell-type-specific gene expression programs, most often by looping through long distances to come in physical proximity with

3660-559: The two processes, giving time for RNA processing to occur. In most organisms non-coding genes (ncRNA) are transcribed as precursors that undergo further processing. In the case of ribosomal RNAs (rRNA), they are often transcribed as a pre-rRNA that contains one or more rRNAs. The pre-rRNA is cleaved and modified ( 2′- O -methylation and pseudouridine formation) at specific sites by approximately 150 different small nucleolus-restricted RNA species, called snoRNAs. SnoRNAs associate with proteins, forming snoRNPs. While snoRNA part basepair with

3721-454: The versatility and adaptability of any organism. Numerous terms are used to describe types of genes depending on how they are regulated; these include: Any step of gene expression may be modulated, from the DNA-RNA transcription step to post-translational modification of a protein. The stability of the final gene product, whether it is RNA or protein, also contributes to the expression level of

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