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Journal of Cellular and Molecular... Mar 2022Pre-B-cell leukaemia transcription factor (PBX) proteins are a subfamily of evolutionarily conserved, atypical homeodomain transcription factors that belong to the... (Review)
Review
Pre-B-cell leukaemia transcription factor (PBX) proteins are a subfamily of evolutionarily conserved, atypical homeodomain transcription factors that belong to the superfamily of three amino acid loop extension (TALE) homeodomain proteins. Members of the PBX family play crucial roles in regulating multiple pathophysiological processes, such as the development of organs, congenital cardiac defects and carcinogenesis. The dysregulation of PBXs has been shown to be closely associated with many diseases, particularly cancer. However, the detailed mechanisms of PBX dysregulation in cancer progression are still inconclusive. In this review, we summarize the recent advances in the structures, functions and regulatory mechanisms of PBXs, and discuss their underlying mechanisms in cancer progression. We also highlight the great potential of PBXs as biomarkers for the early diagnosis and prognostic evaluation of cancer as well as their therapeutic applications. The information reviewed here may expand researchers' understanding of PBXs and could strengthen the clinical implication of PBXs in cancer treatment.
Topics: Gene Expression Regulation; Homeodomain Proteins; Neoplasms; Pre-B-Cell Leukemia Transcription Factor 1; Transcription Factors
PubMed: 35068042
DOI: 10.1111/jcmm.17196 -
Oncotarget May 2017The HOX and PBX gene families encode transcription factors that have key roles in establishing the identity of cells and tissues in early development. Over the last 20... (Review)
Review
The HOX and PBX gene families encode transcription factors that have key roles in establishing the identity of cells and tissues in early development. Over the last 20 years it has become apparent that they are also dysregulated in a wide range of solid and haematological malignancies and have a predominantly pro-oncogenic function. A key mode of transcriptional regulation by HOX and PBX proteins is through their interaction as a heterodimer or larger complex that enhances their binding affinity and specificity for DNA, and there is growing evidence that this interaction is a potential therapeutic target in malignancies that include prostate, breast, renal, ovarian and lung cancer, melanoma, myeloma, and acute myeloid leukaemia. This review summarizes the roles of HOX and PBX genes in cancer and assesses the therapeutic potential of HOX/PBX dimer inhibition, including the availability of biomarkers for its application in precision medicine.
Topics: Animals; Biomarkers; Cell Transformation, Neoplastic; Homeodomain Proteins; Humans; Molecular Targeted Therapy; Multigene Family; Neoplasms; Protein Binding; Protein Multimerization
PubMed: 28423659
DOI: 10.18632/oncotarget.15971 -
Plant Signaling & Behavior 2015Posttranslational modifications present in the amino-terminal tails of histones play a pivotal role in the chromatin-mediated regulation of gene expression patterns that... (Review)
Review
Posttranslational modifications present in the amino-terminal tails of histones play a pivotal role in the chromatin-mediated regulation of gene expression patterns that control plant developmental transitions. Therefore, the function of protein domains that specifically recognize these histone covalent modifications and recruit chromatin remodeling complexes and the transcriptional machinery to modulate gene expression is essential for a proper control of plant development. Plant HomeoDomain (PHD) motifs act as effectors that can specifically bind a number of histone modifications and mediate the activation or repression of underlying genes. In this review we summarize recent findings that emphasize the crucial role of this versatile family of chromatin "reader" domains in the transcriptional regulation of plant developmental processes such as meiosis and postmeiotic events during pollen maturation, embryo meristem initiation and root development, germination as well as flowering time.
Topics: Flowers; Homeodomain Proteins; Meiosis; Meristem; Nucleosomes; Plant Development
PubMed: 26156103
DOI: 10.4161/15592324.2014.993253 -
Physiological Reviews Oct 2018The homeoprotein family comprises ~300 transcription factors and was long seen as primarily involved in developmental programs through cell autonomous regulation.... (Review)
Review
The homeoprotein family comprises ~300 transcription factors and was long seen as primarily involved in developmental programs through cell autonomous regulation. However, recent evidence reveals that many of these factors are also expressed in the adult where they exert physiological functions not yet fully deciphered. Furthermore, the DNA-binding domain of most homeoproteins contains two signal sequences allowing their secretion and internalization, thus intercellular transfer. This review focuses on this new-found signaling in cell migration, axon guidance, and cerebral cortex physiological homeostasis and speculates on how it may play important roles in early arealization of the neuroepithelium. It also describes the use of homeoproteins as therapeutic proteins in mouse models of diseases affecting the central nervous system, in particular Parkinson disease and glaucoma.
Topics: Animals; Central Nervous System; Epithelium; Homeodomain Proteins; Humans; Signal Transduction; Transcription Factors
PubMed: 30067157
DOI: 10.1152/physrev.00018.2017 -
The New Phytologist Jan 2017Homeodomain-leucine zipper proteins (HD-ZIPs) form a plant-specific family of transcription factors functioning as homo- or heterodimers. Certain members of all four... (Review)
Review
Homeodomain-leucine zipper proteins (HD-ZIPs) form a plant-specific family of transcription factors functioning as homo- or heterodimers. Certain members of all four classes of this family are involved in embryogenesis, the focus of this review. They support auxin biosynthesis, transport and response, which are in turn essential for the apical-basal patterning of the embryo, radicle formation and outgrowth of the cotyledons. They transcriptionally regulate meristem regulators to maintain the shoot apical meristem once it is initiated. Some members are specific to the protoderm, the outermost layer of the embryo, and play a role in shoot apical meristem function. Within classes, homeodomain-leucine zippers tend to act redundantly during embryo development, and there are many examples of regulation within and between classes of homeodomain-leucine zippers. This indicates a complex network of regulation that awaits future experiments to uncover.
Topics: Gene Expression Regulation, Developmental; Homeodomain Proteins; Indoleacetic Acids; Leucine Zippers; Meristem; Plants
PubMed: 27523393
DOI: 10.1111/nph.14132 -
Frontiers in Immunology 2023The mature lymphocyte population of a healthy individual has the remarkable ability to recognise an immense variety of antigens. Instead of encoding a unique gene for... (Review)
Review
The mature lymphocyte population of a healthy individual has the remarkable ability to recognise an immense variety of antigens. Instead of encoding a unique gene for each potential antigen receptor, evolution has used gene rearrangements, also known as variable, diversity, and joining gene segment (V(D)J) recombination. This process is critical for lymphocyte development and relies on recombination-activating genes-1 (RAG1) and RAG2, here collectively referred to as RAG. RAG serves as powerful genome editing tools for lymphocytes and is strictly regulated to prevent dysregulation. However, in the case of dysregulation, RAG has been implicated in cases of cancer, autoimmunity and severe combined immunodeficiency (SCID). This review examines functional protein domains and motifs of RAG, describes advances in our understanding of the function and (dys)regulation of RAG, discuss new therapeutic options, such as gene therapy, for RAG deficiencies, and explore and methods for determining RAG activity and target specificity.
Topics: Homeodomain Proteins; Recombinases; Gene Rearrangement; Lymphocytes; Genes, RAG-1
PubMed: 37497222
DOI: 10.3389/fimmu.2023.1210818 -
Biochimica Et Biophysica Acta Sep 2011Homeodomain proteins are crucial transcription factors for cell differentiation, cell proliferation and organ development. Interestingly, their homeodomain signature... (Review)
Review
Homeodomain proteins are crucial transcription factors for cell differentiation, cell proliferation and organ development. Interestingly, their homeodomain signature structure is important for both their DNA-binding and their nucleocytoplasmic trafficking. The accurate nucleocytoplasmic distribution of these proteins is essential for their functions. We summarize information on (a) the roles of karyopherins for import and export of homeoproteins, (b) the regulation of their nuclear transport during development, and (c) the corresponding complexity of homeoprotein nucleocytoplasmic transport signals. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import.
Topics: Active Transport, Cell Nucleus; Amino Acid Sequence; Animals; Growth and Development; Homeodomain Proteins; Humans; Karyopherins; Models, Biological; Models, Molecular; Molecular Sequence Data; Nuclear Localization Signals; Phosphorylation; Protein Interaction Domains and Motifs; Sequence Homology, Amino Acid; Signal Transduction
PubMed: 21256166
DOI: 10.1016/j.bbamcr.2011.01.013 -
Blood Apr 2023
Topics: Humans; Homeodomain Proteins; Leukemia, Myeloid, Acute; Receptors, Estrogen; Nuclear Matrix-Associated Proteins; Matrix Attachment Region Binding Proteins
PubMed: 37022737
DOI: 10.1182/blood.2022019244 -
Cardiovascular Research Sep 2016Lymphatic vessels have historically been viewed as passive conduits for fluid and immune cells, but this perspective is increasingly being revised as new functions of... (Review)
Review
Lymphatic vessels have historically been viewed as passive conduits for fluid and immune cells, but this perspective is increasingly being revised as new functions of lymphatic vessels are revealed. Emerging evidence shows that lymphatic endothelium takes an active part in immune regulation both by antigen presentation and expression of immunomodulatory genes. In addition, lymphatic vessels play an important role in uptake of dietary fat and clearance of cholesterol from peripheral tissues, and they have been implicated in obesity and arteriosclerosis. Lymphatic vessels within different organs and in different physiological and pathological processes show a remarkable plasticity and heterogeneity, reflecting their functional specialization. In addition, lymphatic endothelial cells (LECs) of different organs were recently shown to have alternative developmental origins, which may contribute to the development of the diverse lymphatic vessel and endothelial functions seen in the adult. Here, we discuss recent developments in the understanding of heterogeneity within the lymphatic system considering the organ-specific functional and molecular specialization of LECs and their developmental origin.
Topics: Animals; Cardiovascular System; Endothelial Cells; Endothelium, Lymphatic; Homeodomain Proteins; Humans; Lymphatic Vessels; Tumor Suppressor Proteins
PubMed: 27357637
DOI: 10.1093/cvr/cvw175 -
Nucleic Acids Research Jul 2023Homeodomain proteins constitute one of the largest families of metazoan transcription factors. Genetic studies have demonstrated that homeodomain proteins regulate many...
Homeodomain proteins constitute one of the largest families of metazoan transcription factors. Genetic studies have demonstrated that homeodomain proteins regulate many developmental processes. Yet, biochemical data reveal that most bind highly similar DNA sequences. Defining how homeodomain proteins achieve DNA binding specificity has therefore been a long-standing goal. Here, we developed a novel computational approach to predict cooperative dimeric binding of homeodomain proteins using High-Throughput (HT) SELEX data. Importantly, we found that 15 of 88 homeodomain factors form cooperative homodimer complexes on DNA sites with precise spacing requirements. Approximately one third of the paired-like homeodomain proteins cooperatively bind palindromic sequences spaced 3 bp apart, whereas other homeodomain proteins cooperatively bind sites with distinct orientation and spacing requirements. Combining structural models of a paired-like factor with our cooperativity predictions identified key amino acid differences that help differentiate between cooperative and non-cooperative factors. Finally, we confirmed predicted cooperative dimer sites in vivo using available genomic data for a subset of factors. These findings demonstrate how HT-SELEX data can be computationally mined to predict cooperativity. In addition, the binding site spacing requirements of select homeodomain proteins provide a mechanism by which seemingly similar AT-rich DNA sequences can preferentially recruit specific homeodomain factors.
Topics: Animals; Binding Sites; DNA; Homeodomain Proteins; High-Throughput Nucleotide Sequencing
PubMed: 37114997
DOI: 10.1093/nar/gkad318