Lymphoid enhancer-binding factor 1 (LEF1) is a protein that in humans is encoded by the LEF1 gene. 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 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). 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.
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 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.
Regulation 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. 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. 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 and other kinds of malignancies like colorectal cancer. 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, 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). 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.
Expression in cancer
LEF1 is highly overexpressed and associated with disease progression and poor prognosis in B-cell chronic lymphocytic leukemia and other kinds of malignancies like colorectal cancer. 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 (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. Many of these studies have proven effective in diminishing the growth, migration and invasion rates of tumorigenic cancer cells.
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