Lymphoid enhancer-binding factor 1 (LEF1) is a protein that in humans is encoded by the LEF1 gene. [5] It is a member of T cell factor/lymphoid enhancer factor (TCF/LEF) family.
Lymphoid enhancer-binding factor 1 (LEF1) is a protein that in humans is encoded by the LEF1 gene. [5] It is a member of T cell factor/lymphoid enhancer factor (TCF/LEF) family.
Lymphoid enhancer-binding factor-1 (LEF1) is a 48-kD nuclear protein that is expressed in pre-B and T cells. It binds to a functionally important site in the T-cell receptor-alpha (TCRA) enhancer and confers maximal enhancer activity. LEF1 belongs to a family of regulatory proteins that share homology with high mobility group protein-1 (HMG1). [6]
LEF1 is highly overexpressed and associated with disease progression and poor prognosis in B-cell chronic lymphocytic leukemia [7] and other kinds of malignancies like colorectal cancer. [8] It is also a promising potential drug target. [9]
Lymphoid enhancer-binding factor 1 has been shown to interact with:
Part of the capabilities of the LEF1 family of genes to be implicated in cancer growth is their ability to regulate the epithelial-mesenchymal transition (EMT) process, a cellular pathway by which the inhibition of genes responsible for producing adhesive properties and for polarizing the cell occurs. Though it can be activated independently of β-catenin, much of its effects result from the activation of this protein. When activated by β-catenin, LEF-1 transcription is upregulated and induces the inhibition of the genes which code for polarizing and adhesive properties of the cells. As a result of this LEF/β-catenin-induced inhibition, biochemical transformations take place that allow for heightened migratory and invasive capabilities, increased resistance to apoptosis, and the increased production of components of the extracellular matrix (ECM). [20] Once the LEF1 cells have gained these properties and take on the form of mesenchymal stem cells, they are able to migrate away from their initial sources of attachment and this is when they can begin to exert their cancerous effects.
LEF1 has gained much notability recently for its prevalence in many cancerous pathologies, but even with this increased focus on the mechanisms by which LEF1 and the families of genes it is associated with, many of its downstream effects have not been fully elucidated. As a result, studies are continuing to be published surrounding the LEF1 family of genes, in order to fully expound upon its mechanism of action. [21]
Lymphoid enhancer-binding factor-1 (LEF1) is a 48-kD nuclear protein that is expressed in pre-B and T cells. It binds to a functionally important site in the T-cell receptor-alpha (TCRA) enhancer and confers maximal enhancer activity. LEF1 belongs to a family of regulatory proteins that share homology with high mobility group protein-1 (HMG1). [6] These high mobility groups regulate a vast array of cellular processes through the production of transcription factors, which go on to regulate some of the cells most vital processes, including chromatin remodeling, recombination, DNA replication, DNA repair and transcription. In this shared homology between LEF1 and other members of the HMG family, many of the mechanisms of action that can be seen in the way in which HMG1 interacts with histones, nucleosomes and other chromosomal components can be conferred in how LEF1 regulates many of the same cellular processes, as homology oftentimes helps to infer shared function. In fact, other members of the high mobility group (HMG), including TCF-1, have been shown to possess differential expression at different points within the embryogenesis of murine cells. [22]
In terms of the regulation of LEF1 itself however, a number of enzymes like glycogen synthase kinase 3 (GSK3) and Integrin-linked kinase (ILK) will phosphorylate the β-catenin/(LEF/TCF) complexes, signaling for their activation. As previously mentioned, the signaling of these β-catenin molecules plays a central role in the recruitment and subsequent activation of the LEF/TCF proteins. [23] Working as coregulators of one another, β-catenin and LEF/TCF proteins complex and go on to act downstream of the Wnt signaling pathway, whose ligands are highly expressed in tumors. Recently, some of the upstream molecules present in this Wnt signaling pathway have been elucidated that have connected the missing components. [24] Modern molecular biological techniques helped to identify other upstream regulators of the β-catenin/(LEF/TCF) complex along with GSK3 and ILK, notably casein kinase I ε (CK1-ε). CK1-ε has been shown to be a positive regulator of the β-catenin/(LEF/TCF) complex and even mimics the identity of other proteins in the Wnt signaling pathway, thereby intensifying the effects that LEF and TCF proteins have on the cell.
Along with its role in the regulation of the epithelial-mesenchymal transition (EMT) process, LEF1 has also been shown to be implicated in the processes of cellular senescence and aging. Different isoforms have been studied that have differential effects on these biological processes, once again demonstrating the pervasiveness of this family of genes in many different areas of cellular physiology. The biological process is often linked with the senescense-associated secretory phenotype (SASP), wherein aging cells secrete higher levels of immune modulators, pro-inflammatory cytokines, proteases and other biochemicals. These phenotypes that are implicated with SASP's are linked to other age related pathologies, including Chronic obstructive pulmonary disease (COPD) and Idiopathic pulmonary fibrosis (IPF), amongst a host of other comorbidities. While the short LEF1 isoform has been shown to be associated with exacerbation of the effects of cellular senescence, measurement of the activity of transcription factors/regulons associated with the long LEF1 isoform have demonstrated reversal of signs of cellular senescence through a currently unknown mechanism. Research is still being conducted to elucidate the role of these distinct isoforms in contributing to cellular senescence, but the current research has shown the important role LEF1 plays in regulating the transcription of downstream products associated with a wide range of cellular pathways.
LEF1 is highly overexpressed and associated with disease progression and poor prognosis in B-cell chronic lymphocytic leukemia [7] and other kinds of malignancies like colorectal cancer. [8] It is also a promising potential drug target. [9] Due to its irregular expression common in these forms of cancer, as well as other forms like acute lymphoblastic leukemia (ALL), oral squamous cell carcinoma (OSCC) and even renal cell carcinomas (RCC), LEF1 has been heavily targeted as a drug candidate in a number of different studies. [25] Many of these studies have proven effective in diminishing the growth, migration and invasion rates of tumorigenic cancer cells.
The investigation of the role of LEF1 in regards to aging is of extreme importance, as more effective and longevity based therapeutic interventions could be developed that target LEF1 and associated genes, in order to provide a means of minimizing the effects of age-related pathologies and increasing life span for those who are already at higher risk for other age-related comorbidities. [26] The dysregulation of LEF1 has been shown to be highly correlated with the β-catenin binding domain, leading many researchers to consider the downstream effects of knocking out this binding domain and investigating the subsequent effects. The research has revealed that knocking out this domain downregulates the expression the protein products of the LEF1 gene, and as a result, curtailing many of the deleterious effects rapid LEF1 proliferation and migration can have.
In fact, LEF1 silencing in cases of colorectal cancer has been demonstrated to increase the sensitivity of colorectal cancer cells to a number of Platinum-based drugs, including oxaliplatin, 5-FU and irinotecan. [27] These Pt-based drugs act by inhibiting the synthesis of DNA molecules and covalently modifying molecules by forming DNA adducts. In turn, these drugs are able to promote apoptosis in the cancerous cells. Different isoforms of the LEF1 gene, including the long-form and the short-isoform/truncated dominant negative form (dnLEF1), have been shown to have differential effects on the pathology of colorectal cancer, although higher levels of activation in the Wnt/β-catenin signaling pathway in general are correlated with increased cancer stem cell properties in murine tumors. [28] These associations have far reaching implications in regards to the fields of cancer biology and medicine in general, as the enhanced sensitivity of cancer cells to chemotherapeutic agents upon inhibition of the LEF1 family and the corresponding TCF-1, TCF-2, TCF-3 and TCF-4 genes, allows for the development of more drugs that can target the inhibition of this specific pathway and lower the morbidity and mortality rates for a diverse range of cancerous pathologies.
In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.
In cellular biology, the Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt, pronounced "wint", is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.
Catenins are a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells. The first two catenins that were identified became known as α-catenin and β-catenin. α-Catenin can bind to β-catenin and can also bind filamentous actin (F-actin). β-Catenin binds directly to the cytoplasmic tail of classical cadherins. Additional catenins such as γ-catenin and δ-catenin have been identified. The name "catenin" was originally selected because it was suspected that catenins might link cadherins to the cytoskeleton.
Adenomatous polyposis coli (APC) also known as deleted in polyposis 2.5 (DP2.5) is a protein that in humans is encoded by the APC gene. The APC protein is a negative regulator that controls beta-catenin concentrations and interacts with E-cadherin, which are involved in cell adhesion. Mutations in the APC gene may result in colorectal cancer and desmoid tumors.
Catenin beta-1, also known as β-catenin (beta-catenin), is a protein that in humans is encoded by the CTNNB1 gene.
High-Mobility Group or HMG is a group of chromosomal proteins that are involved in the regulation of DNA-dependent processes such as transcription, replication, recombination, and DNA repair.
α-Catenin (alpha-catenin) functions as the primary protein link between cadherins and the actin cytoskeleton. It has been reported that the actin binding proteins vinculin and α-actinin can bind to alpha-catenin. It has been suggested that alpha-catenin does not bind with high affinity to both actin filaments and the E-cadherin-beta-catenin complex at the same time. It has been observed that when α-catenin is not in a molecular complex with β-catenin, it dimerizes and functions to regulate actin filament assembly, possibly by competing with Arp2/3 protein. α-Catenin exhibits significant protein dynamics. However, a protein complex including a cadherin, actin, β-catenin and α-catenin has not been isolated.
Transcription factor 7-like 2 , also known as TCF7L2 or TCF4, is a protein acting as a transcription factor that, in humans, is encoded by the TCF7L2 gene. The TCF7L2 gene is located on chromosome 10q25.2–q25.3, contains 19 exons. As a member of the TCF family, TCF7L2 can form a bipartite transcription factor and influence several biological pathways, including the Wnt signalling pathway.
Beta-catenin-interacting protein 1 is a protein that is encoded in humans by the CTNNBIP1 gene.
Axin-1 is a protein that in humans is encoded by the AXIN1 gene.
E3 SUMO-protein ligase PIAS4 is one of several protein inhibitor of activated STAT (PIAS) proteins. It is also known as protein inhibitor of activated STAT protein gamma, and is an enzyme that in humans is encoded by the PIAS4 gene.
Segment polarity protein dishevelled homolog DVL-1 is a protein that in humans is encoded by the DVL1 gene.
Secreted frizzled-related protein 1, also known as SFRP1, is a protein which in humans is encoded by the SFRP1 gene.
Protein Wnt-3a is a protein that in humans is encoded by the WNT3A gene.
Wnt inhibitory factor 1 is a protein that in humans is encoded by the WIF1 gene. WIF1 is a lipid-binding protein that binds to Wnt proteins and prevents them from triggering signalling.
Transcription factor 7 is the gene that in humans encodes for the TCF1 protein.
B-cell CLL/lymphoma 9 protein is a protein that in humans is encoded by the BCL9 gene.
Dishevelled (Dsh) is a family of proteins involved in canonical and non-canonical Wnt signalling pathways. Dsh is a cytoplasmic phosphoprotein that acts directly downstream of frizzled receptors. It takes its name from its initial discovery in flies, where a mutation in the dishevelled gene was observed to cause improper orientation of body and wing hairs. There are vertebrate homologs in zebrafish, Xenopus (Xdsh), mice and humans. Dsh relays complex Wnt signals in tissues and cells, in normal and abnormal contexts. It is thought to interact with the SPATS1 protein when regulating the Wnt Signalling pathway.
The TCF/LEF family is a group of genes that encode transcription factors which bind to DNA through a SOX-like high mobility group domain. They are involved in the Wnt signaling pathway, particularly during embryonic and stem-cell development, but also had been found to play a role in cancer and diabetes. TCF/LEF factors recruit the coactivator beta-catenin to enhancer elements of genes they target. They can also recruit members of the Groucho family of corepressors.
Transcription factor 7-like 1, also known as TCF7L1, is a human gene.
In ... zebrafish, reporter transgenes containing the TOPFLASH promoter are expressed in certain Wnt-responsive cell types (...Dorsky et al. 2002).
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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