scholarly journals HOX Gene Aberrant Expression in Skin Melanoma: A Review

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
Gérald E. Piérard ◽  
Claudine Piérard-Franchimont
Keyword(s):  
Protein Interactions ◽  
Hox Genes ◽  
Tumour Progression ◽  
Gene Clusters ◽  
Skin Melanoma ◽  
Protein Protein Interactions ◽  
Cell Nuclei ◽  
Aberrant Expression ◽  
Hox Gene ◽  
Hox Protein

The homeobox family and its subset of HOX gene products represent a family of transcription factors directing DNA-protein and protein-protein interactions. In the embryo, they are central regulators in cell differentiation during morphogenesis. A series of genes of the four HOX gene clusters A, B, C, and D were reported to show aberrant expressions in oncogenesis, particularly in cutaneous malignant melanoma (CMM). They are involved in cell proliferation and progression in the CMM metastatic path. We present relevant peer-reviewed literature findings about the aberrant expression of HOX genes in CMM. The number of CMM cell nuclei exhibiting aberrant HOX protein expression appears correlated with tumour progression.

scholarly journals Methylation in HOX Clusters and Its Applications in Cancer Therapy

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1613 ◽  
Author(s):  
Ana Paço ◽  
Simone Aparecida de Bessa Garcia ◽  
Renata Freitas
Keyword(s):  
Gene Expression ◽  
Cancer Therapy ◽  
Hox Genes ◽  
Treatment Options ◽  
Chemotherapy Resistance ◽  
Migration And Invasion ◽  
Aberrant Expression ◽  
Hox Gene ◽  
Positional Identity ◽  
Near Future

HOX genes are commonly known for their role in embryonic development, defining the positional identity of most structures along the anterior–posterior axis. In postembryonic life, HOX gene aberrant expression can affect several processes involved in tumorigenesis such as proliferation, apoptosis, migration and invasion. Epigenetic modifications are implicated in gene expression deregulation, and it is accepted that methylation events affecting HOX gene expression play crucial roles in tumorigenesis. In fact, specific methylation profiles in the HOX gene sequence or in HOX-associated histones are recognized as potential biomarkers in several cancers, helping in the prediction of disease outcomes and adding information for decisions regarding the patient’s treatment. The methylation of some HOX genes can be associated with chemotherapy resistance, and its identification may suggest the use of other treatment options. The use of epigenetic drugs affecting generalized or specific DNA methylation profiles, an approach that now deserves much attention, seems likely to be a promising weapon in cancer therapy in the near future. In this review, we summarize these topics, focusing particularly on how the regulation of epigenetic processes may be used in cancer therapy.

egl-27 generates anteroposterior patterns of cell fusion in C. elegans by regulating Hox gene expression and Hox protein function

Development ◽  
1999 ◽  
Vol 126 (15) ◽  
pp. 3303-3312 ◽  
Author(s):  
Q. Ch'ng ◽  
C. Kenyon
Keyword(s):  
Gene Expression ◽  
Cell Fusion ◽  
Protein Function ◽  
Hox Genes ◽  
Positional Information ◽  
Cell Fates ◽  
Hox Proteins ◽  
Hox Gene ◽  
C Elegans ◽  
Hox Protein

Hox genes pattern the fates of the ventral ectodermal Pn.p cells that lie along the anteroposterior (A/P) body axis of C. elegans. In these cells, the Hox genes are expressed in sequential overlapping domains where they control the ability of each Pn.p cell to fuse with the surrounding syncytial epidermis. The activities of Hox proteins are sex-specific in this tissue, resulting in sex-specific patterns of cell fusion: in hermaphrodites, the mid-body cells remain unfused, whereas in males, alternating domains of syncytial and unfused cells develop. We have found that the gene egl-27, which encodes a C. elegans homologue of a chromatin regulatory factor, specifies these patterns by regulating both Hox gene expression and Hox protein function. In egl-27 mutants, the expression domains of Hox genes in these cells are shifted posteriorly, suggesting that egl-27 influences A/P positional information. In addition, egl-27 controls Hox protein function in the Pn.p cells in two ways: in hermaphrodites it inhibits MAB-5 activity, whereas in males it permits a combinatorial interaction between LIN-39 and MAB-5. Thus, by selectively modifying the activities of Hox proteins, egl-27 elaborates a simple Hox expression pattern into complex patterns of cell fates. Taken together, these results implicate egl-27 in the diversification of cell fates along the A/P axis and suggest that chromatin reorganization is necessary for controlling Hox gene expression and Hox protein function.

The CALM/AF10 Fusion: Molecular Analysis of the Fusion Transcripts in 13 Cases of AML and ALL; Gene Expression Profiling Reveals HOX Gene Deregulation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2895-2895 ◽  
Author(s):  
Alexandre Krause ◽  
Alexander Kohlmann ◽  
Torsten Haferlach ◽  
Claudia Schoch ◽  
Susanne Schnittger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fusion Protein ◽  
Hox Genes ◽  
Lymphoblastic Leukemia ◽  
Critical Role ◽  
Gene Clusters ◽  
Dominant Negative ◽  
Nucleotide Position ◽  
Gamma Delta ◽  
Hox Gene

Abstract The t(10;11)(p13;q14) is a recurring translocation associated with the CALM/AF10 fusion gene which is found in undifferentiated leukemia, acute myeloid leukemia, acute lymphoblastic leukemia and malignant lymphoma with poor prognosis. The CALM/AF10 fusion protein was reported to be the most common fusion protein in T-ALL with TCR gamma delta rearrangement. We have analyzed samples from 9 patients with different types of leukemia: case 1 (AML M2), case 2 (AML M0), case 3 (Pre T-ALL), case 4 (Acute Undifferentiated Leukemia), case 5 (PreT-ALL), case 6 and 7 (ProT-ALL), case 8 (T-ALL), case 9 (AML), with a t(10;11) translocation suggesting a CALM/AF10-rearrangement. The samples were analyzed for the presence of the CALM/AF10 and AF10/CALM mRNA by RT-PCR and sequence analysis. All these patients were found positive for the CALM/AF10 fusion. In addition, we analyzed a series of twenty-nine patients with T-ALL with gamma delta rearrangement. Among these patients, four were positive for CALM/AF10 transcripts, indicating a high incidence of CALM/AF10 fusions in this group of leukemia. We found three different breakpoints in CALM at nucleotide 1926, 2091 and a new exon, with 106 bases inserted after nt 2064 of CALM in patient 4. In AF10 four breakpoints were identified: at nucleotide position 424, 589, 883 and 979. In seven patients it was also possible to amplify the reciprocal AF10/CALM fusion transcript (case 1, 3, 4, 8, 9, 10 and 11). There was no correlation between disease phenotype and breakpoint location. The patients were 5 to 46 years old (median 25). Ten CALM/AF10 positive patients were further analyzed using oligonucleotide microarrays representing 33,000 different genes (U133 set, Affymetrix). Analysis of microarray gene expression signatures of these patients revealed high expression levels of the homeobox gene MEIS1 and the HOXA cluster genes HOXA1, HOXA4, HOXA5, HOXA7, HOXA9, and HOXA10. The overexpression of HOX genes seen in these CALM/AF10 positive leukemias is reminiscent of the pattern seen in leukemias with rearrangements of the MLL gene, and complex aberrant karyotypes suggesting a common effector pathway (i.e. HOX gene deregulation) for these diverse leukemias. It is known that alhambra, the Drosophila homologue of AF10 can act on polycomb group responsive elements, which play a critical role in the regulation of the HOX gene clusters. It is thus conceivable that the CALM/AF10 fusion proteins acts in a dominant negative fashion on wild type AF10 function relieving the repression that is presumably normally exerted by AF10 on the expression of HOX genes.

scholarly journals Structure, function and inhibition of critical protein–protein interactions involving mixed lineage leukemia 1 and its fusion oncoproteins

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Xin Li ◽  
Yongcheng Song
Keyword(s):  
Structure Function ◽  
Protein Interactions ◽  
Hox Genes ◽  
Mixed Lineage Leukemia ◽  
Fusion Partner ◽  
Wild Type ◽  
Protein Protein Interactions ◽  
Leukemic Transformation ◽  
Chromosome Translocations ◽  
Partner Proteins

AbstractMixed lineage leukemia 1 (MLL1, also known as MLL or KMT2A) is an important transcription factor and histone-H3 lysine-4 (H3K4) methyltransferase. It is a master regulator for transcription of important genes (e.g., Hox genes) for embryonic development and hematopoiesis. However, it is largely dispensable in matured cells. Dysregulation of MLL1 leads to overexpression of certain Hox genes and eventually leukemia initiation. Chromosome translocations involving MLL1 cause ~ 75% of acute leukemia in infants and 5–10% in children and adults with a poor prognosis. Targeted therapeutics against oncogenic fusion MLL1 (onco-MLL1) are therefore needed. Onco-MLL1 consists of the N-terminal DNA-interacting domains of MLL1 fused with one of > 70 fusion partners, among which transcription cofactors AF4, AF9 and its paralog ENL, and ELL are the most frequent. Wild-type (WT)- and onco-MLL1 involve numerous protein–protein interactions (PPI), which play critical roles in regulating gene expression in normal physiology and leukemia. Moreover, WT-MLL1 has been found to be essential for MLL1-rearranged (MLL1-r) leukemia. Rigorous studies of such PPIs have been performed and much progress has been achieved in understanding their structures, structure–function relationships and the mechanisms for activating gene transcription as well as leukemic transformation. Inhibition of several critical PPIs by peptides, peptidomimetic or small-molecule compounds has been explored as a therapeutic approach for MLL1-r leukemia. This review summarizes the biological functions, biochemistry, structure and inhibition of the critical PPIs involving MLL1 and its fusion partner proteins. In addition, challenges and perspectives of drug discovery targeting these PPIs for the treatment of MLL1-r leukemia are discussed.

scholarly journals Rapid genomic DNA variation in newly hybridized carp lineages derived from Cyprinus carpio (♀) × Megalobrama amblycephala (♂)

2019 ◽  
Author(s):  
Kaikun Luo ◽  
Shi Wang ◽  
Yeqing Fu ◽  
Pei Zhou ◽  
Xuexue Huang ◽  
...  
Keyword(s):  
Common Carp ◽  
Genomic Dna ◽  
First Generation ◽  
Second Generation ◽  
Hox Genes ◽  
Gene Clusters ◽  
Megalobrama Amblycephala ◽  
Distant Hybridization ◽  
Hox Gene ◽  
Blunt Snout Bream

Abstract Background: Distant hybridization can generate changes in phenotypes and genotypes that lead to the formation of new hybrid lineages with genetic variation. In this study, based on the establishment of two bisexual fertile carp lineages, including the improved diploid common carp (IDC) lineage and the improved diploid scattered mirror carp (IDMC) lineage, from the interspecific hybridization of common carp (Cyprinus carpio, 2n = 100) (♀) × blunt snout bream (Megalobrama amblycephala, 2n = 48) (♂), provided a good platform to investigate the relationship of genetic and variation between the parents and their hybrid progenies. Result: In this study, we investigated the genetic variation of 12 Hox genes in the two types of carp lineages derived from common carp (♀) × blunt snout bream (♂). Hox gene clusters were abundant in the first generation of IDC, but most were not stably inherited in the second generation. In contrast, we did not find obvious mutations in Hox genes in the first generation of IDMC, and almost all the Hox gene clusters were stably inherited from the first generation to the second generation of IDMC. Interestingly, we found obvious recombinant clusters of Hox genes in both carp lineages, and partially recombinant clusters of Hox genes were stably inherited from the first generation to the second generation in both types of carp lineages. On the other hand, some Hox genes were gradually becoming pseudogenes, and some genes were completely pseudogenised in IDC or IDMC. Conclusions: Our results provided important evidence that distant hybridization produces rapid genomic DNA changes that may or may not be stably inherited, providing novel insights into the function of hybridization in the establishment of improved lineages used as new fish resources for aquaculture.

scholarly journals Hox Gene Collinearity May Be Related to Noether Theory on Symmetry and Its Linked Conserved Quantity

J ◽  
2020 ◽  
Vol 3 (2) ◽  
pp. 151-161
Author(s):  
Spyros Papageorgiou
Keyword(s):  
Hox Genes ◽  
Fundamental Property ◽  
Gene Clusters ◽  
Strand Break ◽  
Early Embryo ◽  
Conserved Quantity ◽  
Biophysical Model ◽  
Self Similarity ◽  
Hox Gene ◽  
Hox Clusters

Hox Gene Collinearity (HGC) is a fundamental property that controls the development of many animal species, including vertebrates. In the Hox gene clusters, the genes are located in a sequential order Hox1, Hox2, Hox3, etc., along the 3’ to 5’ direction of the cluster in the chromosome. During Hox cluster activation, the Hox genes are expressed sequentially in the ontogenetic units D1, D2, D3, etc., along the anterior–posterior axis (A-P) of the early embryo. This collinearity, first observed by E.B. Lewis, is surprising because the spatial collinearity of these structures (Hox clusters and embryos) correlates entities that differ by about four orders of magnitude. Biomolecular mechanisms alone cannot explain such correlations. Long-range physical interactions, such as diffusion or electric attractions, should be involved. A biophysical model (BM) was formulated, which, in alignment with the biomolecular processes, successfully describes the existing vertebrate genetic engineering data. One hundred years ago, Emmy Noether made a fundamental discovery in mathematics and physics. She proved, rigorously, that a physical system obeying a symmetry law (e.g., rotations or self-similarity) is followed by a conserved physical quantity. It is argued here that HGC obeys a ‘primitive’ self-similarity symmetry. In this case, the associated primitive conserved quantity is the irreversibly increasing ‘ratchet’-like Hoxgene ordering where some genes may be missing. The genes of a vertebrate Hox clusterare located along a finite straight line. The same order follows the ontogenetic unitsof the vertebrate embryo. Therefore, HGC is a manifestation of a primitive Noether Theory (NT). NT may be applied to other than the vertebrate case, for instance, to animals with a circular topological symmetry. For example, the observed abnormal Hox gene ordering of the echinoderm Hox clusters may be reproduced by a double-strand break of the circular Hox gene ordering and its subsequent incorporation in the flanking chromosome.

scholarly journals Making the LINC: SUN and KASH protein interactions

2015 ◽  
Vol 396 (4) ◽  
pp. 295-310 ◽  
Author(s):  
Dae In Kim ◽  
Birendra KC ◽  
Kyle J. Roux
Keyword(s):  
Protein Interactions ◽  
Nuclear Membrane ◽  
Comprehensive Analysis ◽  
Linc Complex ◽  
Protein Protein Interactions ◽  
Cell Nuclei ◽  
Cellular Functions ◽  
The Core ◽  
Sun Domain ◽  
Critical Structure

Abstract Cell nuclei are physically integrated with the cytoskeleton through the linker of nucleoskeleton and cytoskeleton (LINC) complex, a structure that spans the nuclear envelope to link the nucleoskeleton and cytoskeleton. Outer nuclear membrane KASH domain proteins and inner nuclear membrane SUN domain proteins interact to form the core of the LINC complex. In this review, we provide a comprehensive analysis of the reported protein-protein interactions for KASH and SUN domain proteins. This critical structure, directly connecting the genome with the rest of the cell, contributes to a myriad of cellular functions and, when perturbed, is associated with human disease.

scholarly journals Identification of New Protein-Protein Interactions Involving the Products of the Chromosome- and Plasmid-Encoded Type IV Secretion Loci of the Phytopathogen Xanthomonas axonopodis pv. citri

2005 ◽  
Vol 187 (7) ◽  
pp. 2315-2325 ◽  
Author(s):  
Marcos C. Alegria ◽  
Diorge P. Souza ◽  
Maxuel O. Andrade ◽  
Cassia Docena ◽  
Leticia Khater ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Gene Clusters ◽  
Hypothetical Protein ◽  
Type Iv Secretion ◽  
Open Reading Frames ◽  
Protein Protein Interactions ◽  
Xanthomonas Axonopodis ◽  
Type Iv ◽  
Acid Domain ◽  
Amino Acid Domain

ABSTRACT The recently sequenced genome of the bacterial plant pathogen Xanthomonas axonopodis pv. citri contains two virB gene clusters, one on the chromosome and one on a 64-kb plasmid, each of which codes for a previously uncharacterized type IV secretion system (T4SS). Here we used a yeast two-hybrid assay to identify protein-protein interactions in these two systems. Our results revealed interactions between known T4SS components as well as previously uncharacterized interactions involving hypothetical proteins coded by open reading frames in the two X. axonopodis pv. citri virB loci. Our results indicate that both loci may code for previously unidentified VirB7 proteins, which we show interact with either VirB6 or VirB9 or with a hypothetical protein coded by the same locus. Furthermore, a set of previously uncharacterized Xanthomonas proteins have been found to interact with VirD4, whose gene is adjacent to the chromosomal virB locus. The gene for one member of this family is found within the chromosomal virB locus. All these uncharacterized proteins possess a conserved 120-amino-acid domain in their C termini and may represent a family of cofactors or substrates of the Xanthomonas T4SS.

scholarly journals Proximity-dependent biotinylation to elucidate the interactome of TNK2 non-receptor tyrosine kinase

2021 ◽  
Author(s):  
Raiha Tahir ◽  
Anil K Madugundu ◽  
Savita Udainiya ◽  
Jevon A. Cutler ◽  
Santosh Renuse ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Isotope Labeling ◽  
Molecular Mapping ◽  
Immunoblot Analysis ◽  
Protein Protein Interactions ◽  
Aberrant Expression ◽  
Interacting Protein ◽  
Increased Sensitivity

Non-receptor tyrosine kinases represent an important class of signaling molecules which are involved in driving diverse cellular pathways. Although, the large majority have been well-studied in terms of their protein-binding partners, the interactomes of some of the key non-receptor tyrosine kinases such as TNK2 (also known as activated Cdc42-associated kinase 1 or ACK1) have not been systematically investigated. Aberrant expression and hyperphosphorylation of TNK2 has been implicated in a number of cancers. However, the exact proteins and cellular events that mediate phenotypic changes downstream of TNK2 are unclear. Biological systems that employ proximity-dependent biotinylation methods, such as BioID, are being increasingly used to map protein-protein interactions as they provide increased sensitivity in discovering interaction partners. In this study, we employed BioID coupled to the biotinylation site identification technology (BioSITe) method that we recently developed to perform molecular mapping of intracellular proteins associated with TNK2. We also employed stable isotope labeling with amino acids in cell culture (SILAC) to quantitatively explore the interactome of TNK2. By performing a controlled comparative analysis between full-length TNK2 and its truncated counterpart, we were not only able to confidently identify site-level biotinylation of previously well-established TNK2 binders and substrates such as NCK1, NCK2, CTTN, STAT3, but also discover several novel TNK2 interacting partners. We validated TNK2 interaction with one of the novel TNK2 interacting protein, clathrin interactor 1 (CLINT1), using immunoblot analysis. Overall, this work reveals the power of the BioSITe method coupled to BioID and highlights several molecules that warrant further exploration to assess their functional significance in TNK2-mediated signaling.

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