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Upstream stimulatory factor 1 is a protein that in humans is encoded by the USF1 gene. [5] [6]
The upstream stimulatory factor gene encodes a transcription factor USF that belongs to the proto-oncogene MYC family and is featured by a basic helix-loop-helix leucine zipper (bHLH-LZ) motif in the protein structure. [7] USF was originally identified to regulate the major late promoters of adenovirus, and recent research has further revealed its role in tissue protection. [7] The bHLH-LZ motif enables the transactivation capacity of the USF protein through interacting with the Initiator element (Inr) and E-box motif on the bound DNA. [7] [8] In the context of insulin and glucose-induced USF activities, those E-box motifs can act as a glucose-responsive element (GRE) and a part of the carbohydrate response element (ChoRE) to interact with transcription factors. [8]
USF comprises two major isoforms: USF1 and USF2. USF1 gene locates on the chromosome region 1q22-q23 in both human and mice; USF2 gene locates on the chromosome 19q13 in human and chromosome 19q7 in mice, respectively. [9] Both USF1 and USF2 transcripts comprise 10 exons and can undergo exon 4-excision during alternative splicing. [7] [9] From an auto-regulation perspective, these exon 4-excision products act as dominant negative regulators and are found to suppress USF-dependent gene expression. [7] [9]
Although USF1 and USF2 share 70% of the amino acid sequence in their bHLH-LZ region, only 40% of similarity is found in their full-length proteins. In addition, USF1 and USF2 exhibit different protein abundances in a cell type-specific manner. [7] It has been found that USF1 and USF2 expression increases during the differentiation of erythroid cells. [10] Despite the ubiquitous expression of both isoforms, USF1 and USF2 mediate different biological processes and functions in cells. While USF1 modulates metabolism, immune response, and tissue protection, USF2 primarily controls embryonic development, brain function, iron metabolism, and fertility. [7] Structurally, the highly conserved bHLH-LZ structure on the C-terminus of USF yields high binding specificity and promotes the formation of USF1 homodimers or USF1-USF2 heterodimers for DNA binding. [7] [9] [11] The USF-specific region (USR) on the N-terminal region, on the other hand, facilitates the nuclear translocation and activation of USF1.
This gene encodes a member of the basic helix-loop-helix leucine zipper family and can function as a cellular transcription factor. The encoded protein can activate transcription through pyrimidine-rich initiator (Inr) elements and E-box motifs. This gene has been linked to familial combined hyperlipidemia (FCHL). Two transcript variants encoding distinct isoforms have been identified for this gene. [6]
A study of mice suggested reduced USF1 levels increase metabolism in brown fat. [12]
The symmetrical E-box motif is the main target of bHLH-LZ transcription factors, and USF1 has a high binding affinity for the core sequence CACGTG in the motif. [9] USF1-DNA binding activity can be modulated by cell type-specific DNA methylation and acetylation on the E-box motif or by post-transcriptional modifications of the USF1 protein. For example, CpG methylation on the central E-box motif inhibits the complex formation of USF1 with its co-transcription factors and therefore decreases the corresponding gene expression in mouse lymphosarcoma cells. [9] In contrast, phosphorylation of USF1 by p38 mitogen-activated protein kinases, protein kinase A or protein kinase C increases its binding to the E-box motif and activate gene transcription. [9]
Mitogen-activated protein kinase (MAPKs) phosphorylates serine and threonine residues of substrate proteins and convert extracellular signals induced by growth factors, mitogens or cytokines into intracellular phosphorylation cascades, which regulate cell proliferation, differentiation, stress responses and apoptosis (programmed cell death). [7]
Phosphorylation by MAPKs induces a conformational change of the USF protein and exposes its DNA-binding domain for interaction. This increased structural exposure enhances DNA binding and therefore the transcriptional activity of USF. [13]
Proteins mediating USF1 modification | |
---|---|
Phosphorylation | p38, pKA and pKC, [9] ERK1/2, [13] DNA-PK [11] |
Acetylation | PCAF [11] |
Methylation' | SET7/92 [9] |
USF1-interacting proteins | |
Transcription co-factors | USF2, [7] SP1, PEA3, MTF1, [9] SREBP1-c, [11] MED17, [15] BAF60 [15] |
Interaction between USF1 and other transcription factors, including SP1, PEA3 (also known as ETV4) and MTF1, also leads to cooperative transcriptional regulation. For instance, the leucine zipper motif of USF1 recruits PEA3 to form a ternary complex and co-regulates the transcription of BAX, an apoptosis regulator. [9] Another USF1-regulated target is topoisomerase III (hTOP3⍺), which catalyzes the topological changes of DNA, modifies DNA supercoil structures, and increases the chromatin accessibility for gene expression. [9] Similar interactions exist between USF1 and JMJD1C or H3K9 demethylase, in which the molecular interactions change chromatin accessibility and elevate the transcription of a series of lipogenic genes, including FASN , ACC, ACLY, and SREBP1. [15]
Chromosomes are generally classified into euchromatin and heterochromatin with distinct histone modifications, compaction levels, and the resulting gene expression patterns. Heterochromatin is a tightly condensed and transcriptionally repressed chromatin domain that is characterized by distinct combinations of histone post-translational modifications. [17] Heterochromatin is required for genome stability and gene expression regulation. However, it can spread into neighboring DNA regions and inactivate gene expression. [17] [18] Chromosome boundary elements are thus necessary to block such stochastic spreads of heterochromatin and maintain stable gene expression. [19] USF1 and USF2 have been found to recruit various histone-modifying complexes, including the histone H3 methyltransferase Set1 complex and the H4 arginine 3 methyltransferase PRMT1, with the latter known to establish active chromatin domains. [19] USF1/USF2 binding deposits a high level of activating histone modifications on adjacent nucleosomes and thus prevents the propagation of chromatin silencing modifications from the heterochromatin, such as H3K9 and K27 methylation. [19]
Other USF1/USF2-related chromatin modifications include the recruitment of the E3 ubiquitin ligase, RNF20, to moniubiquitinate histone H2B. [19] The loss of RNF20 is found to cause an extension of the silencing modifications from the 16 kb heterochromatic domain into the β-globin locus. [19] Moreover, USF1 and USF2 can bind to the 5' DNase I hypersensitive site HS4 and recruit an H3 acetyltransferase, PCAF, which blocks the heterochromatin spread into the β-globin locus. [18]
USF is known to bind the L-type pyruvate kinase promoter on DNA at high glucose and insulin levels. Excessive insulin activates kinases and phosphatases that post-translationally modify USF, sterol regulatory element-binding protein 1C (SREBP1C), Carbohydrate-responsive element-binding protein (ChREBP), and Liver X receptor (LXRs). [11] With insulin stimulation, USF1 and USF2 bind to the E-boxes at -332 and -65 in the promoter region of FASN that encodes Fatty acid synthase (FAS) for lipogenesis. [11]
Various post-translational modifications of USF1 determine its activity and signaling pathways and can affect the lipogenesis process. An abnormal increase in the USF-mediated de novo fatty acid synthesis is found to cause intracellular fatty acid accumulation and deregulate gene expression and cellular processes like tumor cell survival. [20]
USF1 transcription undergoes active dynamics during cell meiosis, in which the USF1 mRNA first increases significantly during 2-8 cells and then decreases to an undetectable level at the blastocyst stage, indicating its role in the embryo genome activation. [22] USF1 siRNA knockout has been shown to compromise the blastocyst rate and deregulate the transcripts of twist-related protein 2 (increased), growth differentiation factor-9 and follistatin (decreased) by affecting their promoter-binding element E-box region during oocyte maturation. [22]
Diabetic kidney disease (DKD) (or Diabetic nephropathy) is a progressive microalbuminuria disease with a slight loss of albumin in the urine (30–300 mg per day); DKD has been viewed as a diabetic complication-related microvascular disorder in a renal manifestation. [23] In kidney biopsy, DKD is characterized by glomerular and tubular basement thickening, mesangial expansion, glomerulosclerosis, podocyte effacement (histology) and nephron loss. [24] DKD occurs in 30%-50% of the diabetic patient population and leads to kidney failures in up to 20% of the type 1 diabetic patients. [24] However, a substantial portion of DKD patients do not manifest albuminuria. [24] DKD pathogenesis is attributed to the dysregulated glucose transport at a higher glucose level and the excessive influx of intracellular glucose into endothelial cells. [23] The elevated glucose level is sustained along with multiple metabolic phenotypes such as excess fatty acids and oxidative stress, as well as shear stress es induced by hypertension and hyperfusion, and can lead to microvascular rarefaction, hypoxia and maladaptation in glomerular neoangiogenesis. [23]
USF1 as an insulin-sensitive transcription factor that becomes active in response to a high glucose level promotes the transactivation of genes involved in lipid metabolism, including hepatic lipase (LIPC), hepatocyte nuclear factor 4 alpha (HNF4A), Apolipoprotein AI (APOA1), Apolipoprotein L1 (APOL1 ) and Haptoglobin-related protein (HPR). [25] Especially, APOL1 is known to complex with APOA-I and HDL to facilitate cell autophagy in response to injuries and prevent glomerular diseases; however, an APOL1 risk variant specific to podocyte inhibits cell autophagy and can trigger kidney disease. [25]
Cancer cells exhibit a set of phenotypes, including a highlighted increase in aerobic glycolysis, lactic acid production (known as the Warburg effect), elevated protein and DNA synthesis, and increased de novo or endogenous fatty acid synthesis by fatty acid synthase (FAS). [20] FAS synthesizes primarily palmitate from malonyl-CoA, which is further esterified to triglycerides for energy storage. Normally, FASN is active during embryogenesis and in fetal lungs for lubricant production; however, it is physiologically low-expressed in non-cancerous adult cells. In contrast, abnormal FASN overexpression is detected in multiple cancer types, spanning breast cancer, colorectal cancer, prostate cancer, pancreatic cancer and ovarian cancer. [26] FASN-mediated de novo lipid synthesis accounts for more than 93% of triglycerides in tumor cells. [20] Specifically, tumor cells prefer glycolysis over oxidation for energy consumption and re-direct the glycolytic products towards de novo fatty acid synthesis to supply lipids for membrane production and protein lipidation for fast cell proliferation. [20] For example, PI3K-AKT pathway is found to increase in LNCaP prostate cancer cells to stimulate FASN overexpression. Concurrently, fatty acid synthase overexpression is also post-translationally sustained by USP2 a-mediated ubiquitination reduction, stabilizing FAS for constitutive signal transduction. [20] In addition to de novo lipogenesis, FAS promotes the localization of VEGFR-2 to the lipid raft of the endothelial cell membrane and thus enhances angiogenesis in tumor development. [26] Meanwhile, mutual activation between FAS and ERBB2 (HER2) signaling also potentiates tumorigenesis, in which ERBB2 amplification is associated with elevated survival and proliferation of cancer cells and poor prognosis in breast and gastric cancers; an ERBB2 increase, especially, contributes to 18-25% of breast cancers. [27] In prostate cancer cells and promyelocytic leukemia cells, USF1 activation also attains a high-level of PAI-1 expression and inhibits spontaneous or camptothecin-induced apoptosis. [13]
The poor prognosis of gastric cancers is associated with low expression of USF1 and p53. [28] Among gastric cancer patients, 88% of the patients are diagnosed with H. pylori infection, and half of the patients show lower USF1 expression in tumor tissues. Mechanistically, H. pylori induces DNA hypermethylation in the promoter regions of USF1 and USF2 and inhibits expression. Decreased expression reduces the interaction between USF1 and p53 when DNA damage occurs, rendering p53 to associate more frequently with the E3-ubiquitin ligase HDM2 (also known as MDM2) and increasing p53 instability in cancer cells. [28]
Familial combined hyperlipidemia (FCHL) was first used to describe lipid abnormalities in 47 Seattle pedigree-containing members with hypercholesterolemia and hypertriglyceridemia. [29] The core FCHL lipid profiles feature high serum cholesterol/triglyceride, apolipoprotein B (APOB) and LDL levels. Genetic evidence has suggested a FCHL-related locus on the human chromosome 1q21-q23, which is linked to metabolic syndromes. [30] Fine-mapping of those linked regions identifies USF1 as the first positionally cloned gene for FCHL and a target for FCHL treatment. In addition, hepatocyte nuclear factor 4 alpha (HNF4A) is also implicated in high lipid levels and metabolic syndromes. Cooperative effects of USF1 and HNF4A have been shown to regulate the expression of apolipoprotein A-II (APOA2) and apolipoprotein C-III (APOC3). [30] Mutations in USF1, HNF4A and apolipoproteins also increase patients' susceptibility to FCHL. [30] Additional genes subjected to USF1 regulation and involved in glucose/lipid metabolism include apolipoprotein A5 ( APOA5 ), apolipoprotein E (APOE), hormone-sensitive lipase (LIPE), hepatic lipase (LIPC), glucokinase (GCK), islet-specific glucose-6-phosphatase catalytic-subunit-related protein (IGRP), insulin, glucagon receptor (GCGR) and ATP-binding cassette transporter A1 ( ABCA1 ). [30]
USF1 (human gene) has been shown to interact with USF2, [31] [32] FOSL1 [33] and GTF2I. [34] [35]
In molecular biology, a transcription factor (TF) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The function of TFs is to regulate—turn on and off—genes in order to make sure that they are expressed in the desired cells at the right time and in the right amount throughout the life of the cell and the organism. Groups of TFs function in a coordinated fashion to direct cell division, cell growth, and cell death throughout life; cell migration and organization during embryonic development; and intermittently in response to signals from outside the cell, such as a hormone. There are approximately 1600 TFs in the human genome. Transcription factors are members of the proteome as well as regulome.
In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response. Some examples of this include producing the mRNA that encode enzymes to adapt to a change in a food source, producing the gene products involved in cell cycle specific activities, and producing the gene products responsible for cellular differentiation in multicellular eukaryotes, as studied in evolutionary developmental biology.
5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. It belongs to a highly conserved eukaryotic protein family and its orthologues are SNF1 in yeast, and SnRK1 in plants. It consists of three proteins (subunits) that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. In response to binding AMP and ADP, the net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, inhibition of adipocyte lipolysis, and modulation of insulin secretion by pancreatic β-cells.
A basic helix–loop–helix (bHLH) is a protein structural motif that characterizes one of the largest families of dimerizing transcription factors. The word "basic" does not refer to complexity but to the chemistry of the motif because transcription factors in general contain basic amino acid residues in order to facilitate DNA binding.
In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride synthesis, with the latter being the process by which fatty acids are esterified to glycerol before being packaged into very-low-density lipoprotein (VLDL). Fatty acids are produced in the cytoplasm of cells by repeatedly adding two-carbon units to acetyl-CoA. Triacylglycerol synthesis, on the other hand, occurs in the endoplasmic reticulum membrane of cells by bonding three fatty acid molecules to a glycerol molecule. Both processes take place mainly in liver and adipose tissue. Nevertheless, it also occurs to some extent in other tissues such as the gut and kidney. A review on lipogenesis in the brain was published in 2008 by Lopez and Vidal-Puig. After being packaged into VLDL in the liver, the resulting lipoprotein is then secreted directly into the blood for delivery to peripheral tissues.
Zinc finger protein GLI1 also known as glioma-associated oncogene is a protein that in humans is encoded by the GLI1 gene. It was originally isolated from human glioblastoma cells.
Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene.
Protein c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It is encoded in humans by the FOS gene. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV. It is a part of a bigger Fos family of transcription factors which includes c-Fos, FosB, Fra-1 and Fra-2. It has been mapped to chromosome region 14q21→q31. c-Fos encodes a 62 kDa protein, which forms heterodimer with c-jun, resulting in the formation of AP-1 complex which binds DNA at AP-1 specific sites at the promoter and enhancer regions of target genes and converts extracellular signals into changes of gene expression. It plays an important role in many cellular functions and has been found to be overexpressed in a variety of cancers.
Activator protein 1 (AP-1) is a transcription factor that regulates gene expression in response to a variety of stimuli, including cytokines, growth factors, stress, and bacterial and viral infections. AP-1 controls a number of cellular processes including differentiation, proliferation, and apoptosis. The structure of AP-1 is a heterodimer composed of proteins belonging to the c-Fos, c-Jun, ATF and JDP families.
An E-box is a DNA response element found in some eukaryotes that acts as a protein-binding site and has been found to regulate gene expression in neurons, muscles, and other tissues. Its specific DNA sequence, CANNTG, with a palindromic canonical sequence of CACGTG, is recognized and bound by transcription factors to initiate gene transcription. Once the transcription factors bind to the promoters through the E-box, other enzymes can bind to the promoter and facilitate transcription from DNA to mRNA.
Protein C-ets-1 is a protein that in humans is encoded by the ETS1 gene. The protein encoded by this gene belongs to the ETS family of transcription factors.
Sterol regulatory element-binding transcription factor 1 (SREBF1) also known as sterol regulatory element-binding protein 1 (SREBP-1) is a protein that in humans is encoded by the SREBF1 gene.
Heat shock factor 1 is a protein that in humans is encoded by the HSF1 gene. HSF1 is highly conserved in eukaryotes and is the primary mediator of transcriptional responses to proteotoxic stress with important roles in non-stress regulation such as development and metabolism.
Nuclear respiratory factor 1, also known as Nrf1, Nrf-1, NRF1 and NRF-1, encodes a protein that homodimerizes and functions as a transcription factor which activates the expression of some key metabolic genes regulating cellular growth and nuclear genes required for respiration, heme biosynthesis, and mitochondrial DNA transcription and replication. The protein has also been associated with the regulation of neurite outgrowth. Alternate transcriptional splice variants, which encode the same protein, have been characterized. Additional variants encoding different protein isoforms have been described but they have not been fully characterized. Confusion has occurred in bibliographic databases due to the shared symbol of NRF1 for this gene and for "nuclear factor -like 1" which has an official symbol of NFE2L1.
General transcription factor II-I is a protein that in humans is encoded by the GTF2I gene.
Upstream stimulatory factor 2 is a protein that in humans is encoded by the USF2 gene.
Transcriptional enhancer factor TEF-1 also known as TEA domain family member 1 (TEAD1) and transcription factor 13 (TCF-13) is a protein that in humans is encoded by the TEAD1 gene. TEAD1 was the first member of the TEAD family of transcription factors to be identified.
Achaete-scute complex homolog 2 (Drosophila), also known as ASCL2, is an imprinted human gene.
Carbohydrate-responsive element-binding protein (ChREBP) also known as MLX-interacting protein-like (MLXIPL) is a protein that in humans is encoded by the MLXIPL gene. The protein name derives from the protein's interaction with carbohydrate response element sequences of DNA.
Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the FOXO1 gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glycogenolysis by insulin signaling, and is also central to the decision for a preadipocyte to commit to adipogenesis. It is primarily regulated through phosphorylation on multiple residues; its transcriptional activity is dependent on its phosphorylation state.