Lymphoid enhancer-binding factor 1
   HOME

TheInfoList



OR:

Lymphoid enhancer-binding factor 1 (LEF1) is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''LEF1''
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: protei ...
. It is a member of T cell factor/lymphoid enhancer factor ( TCF/LEF) family.


Function

Lymphoid enhancer-binding factor-1 (LEF1) is a 48-kD nuclear protein that is expressed in pre- B and
T cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...
s. 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). These high mobility groups regulate a vast array of cellular processes through the production of
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
s, which go on to regulate some of the cells most vital processes, including
chromatin remodeling Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out ...
, recombination,
DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all life, living organisms, acting as the most essential part of heredity, biolog ...
,
DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ...
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
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes ...
s,
nucleosome A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone, histone proteins and resembles thread wrapped around a bobbin, spool. The nucleosome ...
s 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.


Isoforms

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 Cellular senescence is a phenomenon characterized by the cessation of cell division. In their experiments during the early 1960s, Leonard Hayflick and Paul Moorhead found that normal human fetal fibroblasts in culture reach a maximum of appro ...
and
aging Ageing (or aging in American English) is the process of becoming Old age, older until death. The term refers mainly to humans, many other animals, and fungi; whereas for example, bacteria, perennial plants and some simple animals are potentiall ...
. 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,
protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...
s and other biochemicals. These phenotypes that are implicated with SASP's are linked to other age related pathologies, including Chronic obstructive pulmonary disease (
COPD Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by chronic respiratory symptoms and airflow limitation. GOLD defines COPD as a heterogeneous lung condition characterized by chronic respiratory s ...
) 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.


Regulation

In terms of the regulation of LEF1 itself, however, a number of enzymes like glycogen synthase kinase 3 (
GSK3 Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, glycogen ...
) 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. 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
ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
s 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. 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.


Clinical significance

LEF1 is highly overexpressed and associated with disease progression and poor prognosis in
B-cell chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a type of cancer that affects the blood and bone marrow. In CLL, the bone marrow makes too many lymphocytes, which are a type of white blood cell. In patients with CLL, B cell lymphocytes can begin to colle ...
and other kinds of malignancies like
colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the Colon (anatomy), colon or rectum (parts of the large intestine). Signs and symptoms may include Lower gastrointestinal ...
. It is also a promising potential drug target. 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 Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransm ...
, biochemical transformations take place that allow for heightened migratory and invasive capabilities, increased resistance to
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
, and the increased production of components of the
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...
(ECM). Once the LEF1 cells have gained these properties and take on the form of
mesenchymal stem cell Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells or medicinal signaling cells, are multipotent stromal cells that can Cellular differentiation, differentiate into a variety of cell types, including osteoblasts (bone cells), ...
s, 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.


Expression in cancer

LEF1 is highly overexpressed and associated with disease progression and poor prognosis in
B-cell chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a type of cancer that affects the blood and bone marrow. In CLL, the bone marrow makes too many lymphocytes, which are a type of white blood cell. In patients with CLL, B cell lymphocytes can begin to colle ...
and other kinds of malignancies like
colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the Colon (anatomy), colon or rectum (parts of the large intestine). Signs and symptoms may include Lower gastrointestinal ...
. It is also a promising potential drug target. Due to its irregular expression common in these forms of cancer, as well as other forms like
acute lymphoblastic leukemia Acute lymphoblastic leukemia (ALL) is a cancer of the Lymphocyte, lymphoid line of blood cells characterized by the development of large numbers of lymphoblast, immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, ...
(ALL), oral squamous cell carcinoma (OSCC) and even
renal cell carcinoma Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the Proximal tubule, proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cance ...
s (RCC), LEF1 has been heavily targeted as a drug candidate in a number of different studies. Many of these studies have proven effective in diminishing the growth, migration and invasion rates of tumorigenic cancer cells.


Drug inhibition

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. 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 Platinum is a chemical element; it has Symbol (chemistry), symbol Pt and atomic number 78. It is a density, dense, malleable, ductility, ductile, highly unreactive, precious metal, precious, silverish-white transition metal. Its name origina ...
-based drugs, including
oxaliplatin Oxaliplatin, sold under the brand name Eloxatin among others, is a cancer medication (platinum-based antineoplastic class) used to treat colorectal cancer. It is given by intravenous, infusion into a vein. Common side effects include paresth ...
, 5-FU and
irinotecan Irinotecan, sold under the brand name Camptosar among others, is an anti-cancer medication used to treat colon cancer and small cell lung cancer. For colon cancer it is used either alone or with fluorouracil. For small cell lung cancer it is ...
. These Pt-based drugs act by inhibiting the synthesis of DNA molecules and covalently modifying molecules by forming
DNA adduct In molecular genetics, a DNA adduct is a segment of DNA bound to a Carcinogen, cancer-causing chemical. This process could lead to the development of cancerous cells, or carcinogenesis. DNA adducts in scientific experiments are used as biomarkers ...
s. 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 The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. Members of this subfamily are called murines. In terms of species richness, this subfamily is larger than all mammal families excep ...
tumors. These associations have far reaching implications in regards to the fields of cancer biology and
medicine Medicine is the science and Praxis (process), practice of caring for patients, managing the Medical diagnosis, diagnosis, prognosis, Preventive medicine, prevention, therapy, treatment, Palliative care, palliation of their injury or disease, ...
in general, as the enhanced sensitivity of cancer cells to
chemotherapeutic Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) in a standard regimen. Chemotherapy may be given with a curat ...
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 A disease is a particular abnormal condition that adversely affects the structure or function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical conditions that are asso ...
and mortality rates for a diverse range of cancerous pathologies.


Interactions

Lymphoid enhancer-binding factor 1 has been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization advocating for the legal and human rights of children with intersex traits. The organization was founded in 2006 and fo ...
with: * ALX4, * AML-1, *
Catenin beta-1 Catenin beta-1, also known as β-catenin (''beta''-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. β-Catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcrip ...
/β-catenin/''CTNNB1'', including transgenically, *
EP300 Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 (where E1A = adenovirus early region 1A) also known as EP300 or p300 is an enzyme that, in humans, is encoded by the ''EP300'' gene. It functions as histone ace ...
, *
MITF Microphthalmia-associated transcription factor also known as class E basic helix-loop-helix protein 32 or bHLHe32 is a protein that in humans is encoded by the ''MITF'' gene. MITF is a basic helix-loop-helix leucine zipper transcription factor ...
*
PIAS4 E3 SUMO-protein ligase PIAS4 is one of several protein inhibitor of activated STAT (PIAS) proteins. It is also known as a protein inhibitor of activated STAT protein gamma (PIASg or PIASy), and is an enzyme that in humans is encoded by the ''PIAS4 ...
, *
SMAD2 Mothers against decapentaplegic homolog 2, also known as SMAD family member 2 or SMAD2, is a protein that in humans is encoded by the ''SMAD2'' gene. MAD homolog 2 belongs to the SMAD, a family of proteins similar to the gene products of the ''Dr ...
, and *
SMAD3 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. SMAD3 is a member of the SMAD (protein), SMAD family of proteins. It acts as a mediator of the signal ...
. * ALX4, a protein encoded by the ''ALX4'' gene found predominantly in the
mesenchyme Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood, or bone. The interactions between mesenchyme and epithelium help to form nearly ever ...
of developing embryonic limb buds. This protein is a potent
transcriptional activator A transcriptional activator is a protein (transcription factor) that increases transcription of a gene or set of genes. Activators are considered to have ''positive'' control over gene expression, as they function to promote gene transcription and ...
of the genes required during the development of the skeleton in the appendicular and craniofacial regions during embryonic development. * AML-1, or acute-myeloid leukemia 1 protein, is a protein in humans encoded by the ''RUNX1'' gene. It is also known as runt-related transcription factor 1 (RUNX1) and core-binding factor subunit alpha-2 (CBFA2), and plays an instrumental role in the development of pain-sensing neurons, as well as in the maturation of
hematopoietic stem cell Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within the ...
s into mature
blood cell A blood cell (also called a hematopoietic cell, hemocyte, or hematocyte) is a cell produced through hematopoiesis and found mainly in the blood. Major types of blood cells include red blood cells (erythrocytes), white blood cells (leukocytes), ...
s. It was discovered by Nusslein-Volhard and Wieschaus during a screening of Drosophila in an attempt to elucidate specific mutations dealing with defects in the segmentation patterns and polarization of genes in Drosophila. Similar to the LEF1 interactions, AML-1 has been associated with mutational defects leading to a myriad of blood related pathologies. This list includes Familial Platelet Disorder,
Acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with haematopoiesis, normal blood cell production. Sympt ...
, T-cell acute lymphoblastic leukemia ( T-ALL), and multiple forms of
myelodysplastic A myelodysplastic syndrome (MDS) is one of a group of cancers in which blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may includ ...
neoplasms. *
Catenin beta-1 Catenin beta-1, also known as β-catenin (''beta''-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. β-Catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcrip ...
/β-catenin/''CTNNB1'', including transgenically, as this is a key component of the β-catenin and Wnt signaling pathway that the LEF1 protein plays a role in regulating. This role in transgenic expression has led to a number of studies done using modern
genetic engineering Genetic engineering, also called genetic modification or genetic manipulation, is the modification and manipulation of an organism's genes using technology. It is a set of Genetic engineering techniques, technologies used to change the genet ...
techniques in order to determine the direct role of this Catenin beta-1/LEF1 association in the pathologies listed above. In fact, research has shown that LEF1 and β-catenin, when co-expressed in mammalian cells, combine with DNA in the nucleus to form a
ternary complex A ternary complex is a protein complex containing three different molecules that are bound together. In structural biology, ''ternary complex'' can also be used to describe a crystal containing a protein with two small molecules bound, such as a ...
. In turn, this activates the role of LEF1 as a transcription factor and demonstrates a mechanism by which
signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...
occurs from the Wnt proteins to the nucleus. This protein plays a role in both
gene transcription Transcription is the process of copying a segment of DNA into RNA for the purpose of gene expression. Some segments of DNA are transcribed into RNA molecules that can encode proteins, called messenger RNA (mRNA). Other segments of DNA are transc ...
of DNA to mRNA and
cellular adhesion Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as Cell_junction, cell junc ...
. As referenced earlier, β-catenin plays an integral role in the epithelial-to-mesenchymal transition, acting as a specific signaling molecule called a
morphogen A morphogen is a substance whose non-uniform distribution governs the pattern of tissue development in the process of morphogenesis or pattern formation, one of the core processes of developmental biology, establishing positions of the various ...
which helps guide development of cells in the later stages of embryonic development. Acting in tandem with LEF1, Catenin beta-1 causes certain epithelial cells to loosen their tight associations with the lumen and to adopt a looser and more fluid identity, similar to those seen by cells in the mesenchyme. This loosening of their associations causes the epithelial cells to inactive a number of proteins associated with adhesion and to activate a host of other proteins expressed in resident cells of the mesenchyme. These molecules include
vimentin Vimentin is a structural protein that in humans is encoded by the ''VIM'' gene. Its name comes from the Latin ''vimentum'' which refers to an array of flexible rods. Vimentin is a Intermediate filament#Type III, type III intermediate filamen ...
, alpha smooth muscle actin (
ACTA2 ACTA2 (actin alpha 2) is an actin protein with several aliases including alpha-actin, alpha-actin-2, aortic smooth muscle or alpha smooth muscle actin (α-SMA, SMactin, alpha-SM-actin, ASMA). Actins are a family of globular multi-functional pr ...
) and fibroblast-specific protein 1 ( FSP1). *
EP300 Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 (where E1A = adenovirus early region 1A) also known as EP300 or p300 is an enzyme that, in humans, is encoded by the ''EP300'' gene. It functions as histone ace ...
, *
MITF Microphthalmia-associated transcription factor also known as class E basic helix-loop-helix protein 32 or bHLHe32 is a protein that in humans is encoded by the ''MITF'' gene. MITF is a basic helix-loop-helix leucine zipper transcription factor ...
*
PIAS4 E3 SUMO-protein ligase PIAS4 is one of several protein inhibitor of activated STAT (PIAS) proteins. It is also known as a protein inhibitor of activated STAT protein gamma (PIASg or PIASy), and is an enzyme that in humans is encoded by the ''PIAS4 ...
, *
SMAD2 Mothers against decapentaplegic homolog 2, also known as SMAD family member 2 or SMAD2, is a protein that in humans is encoded by the ''SMAD2'' gene. MAD homolog 2 belongs to the SMAD, a family of proteins similar to the gene products of the ''Dr ...
, and *
SMAD3 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. SMAD3 is a member of the SMAD (protein), SMAD family of proteins. It acts as a mediator of the signal ...
.


References


Further reading

* * * * * * * * * * * * * * * * * * *


External links

* {{Transcription factors, g4 Transcription factors