Protein C-ets-1 is a protein that in humans is encoded by the ETS1 gene. [5] The protein encoded by this gene belongs to the ETS family of transcription factors. [6]
Protein C-ets-1 is a protein that in humans is encoded by the ETS1 gene. [5] The protein encoded by this gene belongs to the ETS family of transcription factors. [6]
There are 28 ETS genes in humans and 27 in mice. They bind the DNA via their winged-helix-turn-helix DNA binding motif known as the Ets domain that specifically recognizes DNA sequences that contain a GGAA/T core element. However, Ets proteins differ significantly in their preference for the sequence flanking the GGAA/T core motif. For instance, the consensus sequence for Ets1 is PuCC/a-GGAA/T-GCPy. On the other hand, many natural Ets1-responsive GGAA/T elements differ from this consensus sequence. The later suggests that several other transcription factors may facilitate Ets1 binding to unfavorable DNA sequences. ChIP-Seq studies have shown that Ets1 can bind both AGGAAG and CGGAAG motifs. [7]
Ets1 binds to DNA as a monomer. Phosphorylation of serine residues of the C-terminal domain (in the nucleotide sequence they belong to exon VII) known as autoinhibition makes Ets1 inactive. There are several ways to activate Ets1. First, Ets1 can be dephosphorylated. Second, two Ets1 can be activated If two Ets molecules homodimerize. The homodimerization occurs if DNA binding sites are present in the correct orientation and spacing. Thus, the exact layout of binding sites within an enhancer or promoter segment to either relieve or allow autoinhibition of Ets1 to occur may strongly influence whether or not Ets1 actually binds to particular site. Third, Ets1 can be activated by Erk2 and Ras at Thr38. The truncated isoform cannot be phosphorylated by the Erk2. It is localized in the cytoplasm and acts as a dominant negative isoform. Contrary, another isoform that misses exon VII is constitutively active. Many Ras responsive genes harbor combinatorial Ets/AP1 recognition motifs through which Ets1 and AP1 synergistically activate transcription when stimulated by Ras. [8]
In adult humans, Ets1 is expressed at high levels mainly in immune tissues such as thymus, spleen, and lymph node (B cells, T cells, NK cells, and NK T cells and non-lymphoid immune cells). An enforced expression of Ets1 blocks differentiation of B- and T-cells. By contrast, knocking Ets1 down causes multiple defects in the immune system.
Ets1 knockout mice have aberrant thymic differentiation, reduced peripheral T cell numbers, reduced IL-2 production, a skewing towards a memory/effector phenotype and impairments in the production of Th1 and Th2 cytokines. Although Ets1 knockout mice have an impaired development of Th1, Th2, and Treg cells, they have higher numbers of Th17 cells. In CD4/CD8 double positive thymocytes from Ets knockout mice, both the suppression of gene expression programs corresponding to alternative lineages and upregulation of T-cell specific genes are impaired. [7] There are also partial defects in bone marrow B cell development with reduced cellularity and inefficient transition from pro-B to pre-B cell stages.
Meta-analyses of multiple genome-wide association studies has suggested an association of SNPs in the ETS1 locus with psoriasis in European populations. This is not surprising because Ets1 is a negative regulator of Th17 cells.
Ets1 overexpression in stratified squamous epithelial cells causes pro-oncogenic changes, such as suspension of terminal differentiation, high secretion of matrix metalloproteases (Mmps), epidermal growth factor ligands, and inflammatory mediators.
Ets1 directly interacts with various transcription factors. Their interaction results in formation of multiprotein complexes. When Ets1 interacts with other transcription factors (Runx1, Pax5, TFE3, and USF1) its final effect on transcription depends on whether C-terminal domain is phosphorylated. Acetyltransferases CBP and p300 bind to the transactivation domain. AP1, STAT5 and VDR bind to C-terminal domain.
Also, ETS1 has been shown to interact with TTRAP, [9] UBE2I [10] and Death associated protein 6. [11]
Importantly, ETS1 was shown to be able to bind both nucleosome-bound and -depleted DNA, with its suppression leading to increases in nucleosomal occupancy at sites normally bound by ETS1. [7]
The messenger RNA and protein levels of DNA repair protein PARP1 are controlled, in part, by the expression level of the ETS1 transcription factor which interacts with multiple ETS1 binding sites in the promoter region of PARP1. [12] The degree to which the ETS1 transcription factor can bind to its binding sites on the PARP1 promoter depends on the methylation status of the CpG islands in the ETS1 binding sites in the PARP1 promoter. [13] If these CpG islands in ETS1 binding sites of the PARP1 promoter are epigenetically hypomethylated, PARP1 is expressed at an elevated level. [13] The high constitutive levels of PARP1 in centenarians, providing more effective DNA repair, is thought to contribute to their unusual longevity. These levels of PARP1 expression are considered to be due to altered epigenetic control of transactivation of PARP1 expression. [14]
As shown by Wilson et al., [15] increased ETS1 expression causes about 50 target genes to increase expression, including DNA repair genes MUTYH , BARD1 , ERCC1 and XPA . Increased ETS1 expression causes resistance to cell killing by cisplatin, the resistance thought to be partly due to increased expression of DNA repair genes.
ETS1 functions are regulated by protein – protein interactions. [16] [17] In particular, ETS1 protein interacts with several DNA repair proteins. ETS1 binds with DNA-dependent protein kinase (DNA-PK) [where the DNA-PK complex is made up of DNA-PKcs and DNA repair Ku (protein), and where Ku itself is a heterodimer of two polypeptides, Ku70 (XRCC6) and Ku80 (XRCC5)]. [17] ETS1 interaction with DNA-PK phosphorylates ETS1. [17] Such phosphorylation of ETS1 alters its target gene repertoire. [18] The Ku80 portion of DNA-PK, acting alone, interacts with ETS1 to down-regulate at least one of its transcriptional activities. [17]
As shown by Legrand et al., [19] ETS1 protein interacts with PARP1 protein. ETS1 activates PARP1, causing poly ADP-ribosylation of PARP1 itself and of other proteins, even in the absence of nicked DNA. PARP1 (without self- poly ADP-ribosylation), in turn, is needed for activation of the transactivating activity of ETS1 on a tested promoter. Active PARP1 subsequently causes poly ADP-ribosylation of ETS1, and this appears to promote ETS1 ubiquitination and proteasomal degradation, preventing excessive activity of ETS1.
In biochemistry, in the biological context of organisms' regulation of gene expression and production of gene products, downregulation is the process by which a cell decreases the production and quantities of its cellular components, such as RNA and proteins, in response to an external stimulus. The complementary process that involves increase in quantities of cellular components is called upregulation.
Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability, and programmed cell death.
Death-associated protein 6 also known as Daxx is a protein that in humans is encoded by the DAXX gene.
Histone-modifying enzymes are enzymes involved in the modification of histone substrates after protein translation and affect cellular processes including gene expression. To safely store the eukaryotic genome, DNA is wrapped around four core histone proteins, which then join to form nucleosomes. These nucleosomes further fold together into highly condensed chromatin, which renders the organism's genetic material far less accessible to the factors required for gene transcription, DNA replication, recombination and repair. Subsequently, eukaryotic organisms have developed intricate mechanisms to overcome this repressive barrier imposed by the chromatin through histone modification, a type of post-translational modification which typically involves covalently attaching certain groups to histone residues. Once added to the histone, these groups elicit either a loose and open histone conformation, euchromatin, or a tight and closed histone conformation, heterochromatin. Euchromatin marks active transcription and gene expression, as the light packing of histones in this way allows entry for proteins involved in the transcription process. As such, the tightly packed heterochromatin marks the absence of current gene expression.
ADP-ribosylation is the addition of one or more ADP-ribose moieties to a protein. It is a reversible post-translational modification that is involved in many cellular processes, including cell signaling, DNA repair, gene regulation and apoptosis. Improper ADP-ribosylation has been implicated in some forms of cancer. It is also the basis for the toxicity of bacterial compounds such as cholera toxin, diphtheria toxin, and others.
Poly [ADP-ribose] polymerase 1 (PARP-1) also known as NAD+ ADP-ribosyltransferase 1 or poly[ADP-ribose] synthase 1 is an enzyme that in humans is encoded by the PARP1 gene. It is the most abundant of the PARP family of enzymes, accounting for 90% of the NAD+ used by the family. PARP1 is mostly present in cell nucleus, but cytosolic fraction of this protein was also reported.
Myb-related protein B is a protein that in humans is encoded by the MYBL2 gene.
Friend leukemia integration 1 transcription factor (FLI1), also known as transcription factor ERGB, is a protein that in humans is encoded by the FLI1 gene, which is a proto-oncogene.
Protein C-ETS2 is a protein that in humans is encoded by the ETS2 gene. The protein encoded by this gene belongs to the ETS family of transcription factors.
Cyclin-A2 is a protein that in humans is encoded by the CCNA2 gene. It is one of the two types of cyclin A: cyclin A1 is expressed during meiosis and embryogenesis while cyclin A2 is expressed in dividing somatic cells.
Transcription factor PU.1 is a protein that in humans is encoded by the SPI1 gene.
ERG is an oncogene. ERG is a member of the ETS family of transcription factors. The ERG gene encodes for a protein, also called ERG, that functions as a transcriptional regulator. Genes in the ETS family regulate embryonic development, cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis.
Zinc finger protein 148 is a protein that in humans is encoded by the ZNF148 gene.
ETS domain-containing protein Elk-4 is a protein that in humans is encoded by the ELK4 gene.
MNT is a Max-binding protein that is encoded by the MNT gene
Poly [ADP-ribose] polymerase 2 is an enzyme that in humans is encoded by the PARP2 gene. It is one of the PARP family of enzymes.
Zinc finger protein 143 is a protein that in humans is encoded by the ZNF143 gene.
In the field of molecular biology, the ETSfamily is one of the largest families of transcription factors and is unique to animals. There are 29 genes in humans, 28 in the mouse, 10 in Caenorhabditis elegans and 9 in Drosophila. The founding member of this family was identified as a gene transduced by the leukemia virus, E26. The members of the family have been implicated in the development of different tissues as well as cancer progression.
Post-transcriptional regulation is the control of gene expression at the RNA level. It occurs once the RNA polymerase has been attached to the gene's promoter and is synthesizing the nucleotide sequence. Therefore, as the name indicates, it occurs between the transcription phase and the translation phase of gene expression. These controls are critical for the regulation of many genes across human tissues. It also plays a big role in cell physiology, being implicated in pathologies such as cancer and neurodegenerative diseases.
Parthanatos is a form of programmed cell death that is distinct from other cell death processes such as necrosis and apoptosis. While necrosis is caused by acute cell injury resulting in traumatic cell death and apoptosis is a highly controlled process signalled by apoptotic intracellular signals, parthanatos is caused by the accumulation of Poly(ADP ribose) (PAR) and the nuclear translocation of apoptosis-inducing factor (AIF) from mitochondria. Parthanatos is also known as PARP-1 dependent cell death. PARP-1 mediates parthanatos when it is over-activated in response to extreme genomic stress and synthesizes PAR which causes nuclear translocation of AIF. Parthanatos is involved in diseases that afflict hundreds of millions of people worldwide. Well known diseases involving parthanatos include Parkinson's disease, stroke, heart attack, and diabetes. It also has potential use as a treatment for ameliorating disease and various medical conditions such as diabetes and obesity.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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