scholarly journals HOX Protein Activity Regulation by Cellular Localization

2021 ◽  
Vol 9 (4) ◽  
pp. 56
Author(s):  
Laure Bridoux ◽  
Françoise Gofflot ◽  
René Rezsohazy
Keyword(s):  
Cellular Localization ◽  
Hox Genes ◽  
Model Organisms ◽  
Post Translational Modification ◽  
Protein Activity ◽  
Hox Proteins ◽  
Protein Protein Interaction ◽  
A Cell ◽  
Cell Type Specific ◽  
Hox Protein

While the functions of HOX genes have been and remain extensively studied in distinct model organisms from flies to mice, the molecular biology of HOX proteins remains poorly documented. In particular, the mechanisms involved in regulating the activity of HOX proteins have been poorly investigated. Nonetheless, based on data available from other well-characterized transcription factors, it can be assumed that HOX protein activity must be finely tuned in a cell-type-specific manner and in response to defined environmental cues. Indeed, records in protein–protein interaction databases or entries in post-translational modification registries clearly support that HOX proteins are the targets of multiple layers of regulation at the protein level. In this context, we review here what has been reported and what can be inferred about how the activities of HOX proteins are regulated by their intracellular distribution.

scholarly journals Axial skeleton anterior-posterior patterning is regulated through feedback regulation between Meis transcription factors and retinoic acid

Development ◽  
2020 ◽  
Vol 148 (1) ◽  
pp. dev193813
Author(s):  
Alejandra C. López-Delgado ◽  
Irene Delgado ◽  
Vanessa Cadenas ◽  
Fátima Sánchez-Cabo ◽  
Miguel Torres
Keyword(s):  
Transcription Factors ◽  
Retinoic Acid ◽  
Hox Genes ◽  
Feedback Regulation ◽  
Axial Skeleton ◽  
Paraxial Mesoderm ◽  
Hox Proteins ◽  
Skeletal Defects ◽  
Hox Protein ◽  
Anterior Posterior

ABSTRACTVertebrate axial skeletal patterning is controlled by co-linear expression of Hox genes and axial level-dependent activity of HOX protein combinations. MEIS transcription factors act as co-factors of HOX proteins and profusely bind to Hox complex DNA; however, their roles in mammalian axial patterning remain unknown. Retinoic acid (RA) is known to regulate axial skeletal element identity through the transcriptional activity of its receptors; however, whether this role is related to MEIS/HOX activity remains unknown. Here, we study the role of Meis in axial skeleton formation and its relationship to the RA pathway in mice. Meis elimination in the paraxial mesoderm produces anterior homeotic transformations and rib mis-patterning associated to alterations of the hypaxial myotome. Although Raldh2 and Meis positively regulate each other, Raldh2 elimination largely recapitulates the defects associated with Meis deficiency, and Meis overexpression rescues the axial skeletal defects in Raldh2 mutants. We propose a Meis-RA-positive feedback loop, the output of which is Meis levels, that is essential to establish anterior-posterior identities and patterning of the vertebrate axial skeleton.

scholarly journals SUMO: From Bench to Bedside

2020 ◽  
Vol 100 (4) ◽  
pp. 1599-1619 ◽  
Author(s):  
Hui-Ming Chang ◽  
Edward T. H. Yeh
Keyword(s):  
Cellular Localization ◽  
Protein Modification ◽  
Redox Regulation ◽  
Biological Processes ◽  
Protein Activity ◽  
Protein Protein Interaction ◽  
The Family ◽  
Lysine Residues ◽  
Sumo Pathway ◽  
Posttranslational Protein Modification

Sentrin/small ubiquitin-like modifier (SUMO) is protein modification pathway that regulates multiple biological processes, including cell division, DNA replication/repair, signal transduction, and cellular metabolism. In this review, we will focus on recent advances in the mechanisms of disease pathogenesis, such as cancer, diabetes, seizure, and heart failure, which have been linked to the SUMO pathway. SUMO is conjugated to lysine residues in target proteins through an isopeptide linkage catalyzed by SUMO-specific activating (E1), conjugating (E2), and ligating (E3) enzymes. In steady state, the quantity of SUMO-modified substrates is usually a small fraction of unmodified substrates due to the deconjugation activity of the family Sentrin/SUMO-specific proteases (SENPs). In contrast to the complexity of the ubiquitination/deubiquitination machinery, the biochemistry of SUMOylation and de-SUMOylation is relatively modest. Specificity of the SUMO pathway is achieved through redox regulation, acetylation, phosphorylation, or other posttranslational protein modification of the SUMOylation and de-SUMOylation enzymes. There are three major SUMOs. SUMO-1 usually modifies a substrate as a monomer; however, SUMO-2/3 can form poly-SUMO chains. The monomeric SUMO-1 or poly-SUMO chains can interact with other proteins through SUMO-interactive motif (SIM). Thus SUMO modification provides a platform to enhance protein-protein interaction. The consequence of SUMOylation includes changes in cellular localization, protein activity, or protein stability. Furthermore, SUMO may join force with ubiquitin to degrade proteins through SUMO-targeted ubiquitin ligases (STUbL). After 20 yr of research, SUMO has been shown to play critical roles in most, if not all, biological pathways. Thus the SUMO enzymes could be targets for drug development to treat human diseases.

Hox repression of a target gene: extradenticle-independent, additive action through multiple monomer binding sites

Development ◽  
2002 ◽  
Vol 129 (13) ◽  
pp. 3115-3126 ◽  
Author(s):  
Ron Galant ◽  
Christopher M. Walsh ◽  
Sean B. Carroll
Keyword(s):  
Binding Sites ◽  
Target Gene ◽  
Target Genes ◽  
Hox Genes ◽  
Regulatory Element ◽  
Morphological Diversity ◽  
Hox Proteins ◽  
Cis Element ◽  
Additive Action ◽  
Hox Protein

Homeotic (Hox) genes regulate the identity of structures along the anterior-posterior axis of most animals. The low DNA-binding specificities of Hox proteins have raised the question of how these transcription factors selectively regulate target gene expression. The discovery that the Extradenticle (Exd)/Pbx and Homothorax (Hth)/Meis proteins act as cofactors for several Hox proteins has advanced the view that interactions with cofactors are critical to the target selectivity of Hox proteins. It is not clear, however, to what extent Hox proteins also regulate target genes in the absence of cofactors. In Drosophila melanogaster, the Hox protein Ultrabithorax (Ubx) promotes haltere development and suppresses wing development by selectively repressing many genes of the wing-patterning hierarchy, and this activity requires neither Exd nor Hth function. Here, we show that Ubx directly regulates a flight appendage-specific cis-regulatory element of the spalt (sal) gene. We find that multiple monomer Ubx-binding sites are required to completely repress this cis-element in the haltere, and that individual Ubx-binding sites are sufficient to mediate its partial repression. These results suggest that Hox proteins can directly regulate target genes in the absence of the cofactor Extradenticle. We propose that the regulation of some Hox target genes evolves via the accumulation of multiple Hox monomer binding sites. Furthermore, because the development and morphological diversity of the distal parts of most arthropod and vertebrate appendages involve Hox, but not Exd/Pbx or Hth/Meis proteins, this mode of target gene regulation appears to be important for distal appendage development and the evolution of appendage diversity.

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.

scholarly journals Hox Proteins in the Regulation of Muscle Development

2021 ◽  
Vol 9 ◽  
Author(s):  
Gabriela Poliacikova ◽  
Corinne Maurel-Zaffran ◽  
Yacine Graba ◽  
Andrew J. Saurin
Keyword(s):  
Protein Function ◽  
Molecular Mechanisms ◽  
Muscle Development ◽  
Hox Genes ◽  
Fruit Fly ◽  
Comprehensive Overview ◽  
Hox Proteins ◽  
Vertebrate Muscle ◽  
Hox Protein ◽  
Vertebrate Skeleton

Hox genes encode evolutionary conserved transcription factors that specify the anterior–posterior axis in all bilaterians. Being well known for their role in patterning ectoderm-derivatives, such as CNS and spinal cord, Hox protein function is also crucial in mesodermal patterning. While well described in the case of the vertebrate skeleton, much less is known about Hox functions in the development of different muscle types. In contrast to vertebrates however, studies in the fruit fly, Drosophila melanogaster, have provided precious insights into the requirement of Hox at multiple stages of the myogenic process. Here, we provide a comprehensive overview of Hox protein function in Drosophila and vertebrate muscle development, with a focus on the molecular mechanisms underlying target gene regulation in this process. Emphasizing a tight ectoderm/mesoderm cross talk for proper locomotion, we discuss shared principles between CNS and muscle lineage specification and the emerging role of Hox in neuromuscular circuit establishment.

scholarly journals Homeobox Protein, Hmx3, in Postnatally Developing Rat Submandibular Glands

2003 ◽  
Vol 51 (3) ◽  
pp. 385-396 ◽  
Author(s):  
Phyllis A. Shaw ◽  
Xu Zhang ◽  
Andrew F. Russo ◽  
Brad A. Amendt ◽  
Scott Henderson ◽  
...  
Keyword(s):  
Salivary Glands ◽  
Submandibular Gland ◽  
Hox Genes ◽  
Progressive Development ◽  
New Class ◽  
Duct Cells ◽  
Homeobox Protein ◽  
A Cell ◽  
The Central Nervous System ◽  
Cell Type Specific

Homeobox-containing (Hox) genes play important roles in development, particularly in the development of neurons and sensory organs, and in specification of body plan. The Hmx gene family is a new class of homeobox-containing genes defined by a conserved homeobox region and a characteristic pattern of expression in the central nervous system that is more rostral than that of the Hox genes. To date, three closely related members of the Hmx family, Hmx1, Hmx2, and Hmx3, have been described. All three Hmx genes are expressed in the craniofacial region of developing embryos. Here we show, for the first time, the expression of the transcription factor Hmx3 in postnatally developing salivary glands. Hmx3 protein is expressed in a cell type-specific manner in rat salivary glands. Hmx3 is present in both the nuclei and cytoplasm of specific groups of duct cells of the submandibular, parotid, and sublingual glands. Hmx3 expression increases during postnatal development of the submandibular gland. The duct cells show increasing concentrations of Hmx3 protein with progressive development of the submandibular gland. In contrast, the acinar cells of the three salivary glands do not exhibit detectable levels of Hmx3 protein.

The lines gene of Drosophila is required for specific functions of the Abdominal-B HOX protein

Development ◽  
1998 ◽  
Vol 125 (7) ◽  
pp. 1269-1274 ◽  
Author(s):  
J. Castelli-Gair
Keyword(s):  
Hox Genes ◽  
Hox Proteins ◽  
Normal Functions ◽  
Transcriptional Cofactors ◽  
Segment Polarity ◽  
Direct Target ◽  
Hox Protein ◽  
Segment Polarity Gene ◽  
Anterior Posterior ◽  
Polarity Gene

The Hox genes encode homeobox transcription factors that control the formation of segment specific structures in the anterior-posterior axis. HOX proteins regulate the transcription of downstream targets acting both as repressors and as activators. Due to the similarity of their homeoboxes it is likely that much of the specificity of HOX proteins is determined by interaction with transcriptional cofactors, but few HOX cofactor proteins have yet been described. Here I present genetic evidence showing that lines, a segment polarity gene of Drosophila, is required for the function of the Abdominal-B protein. In lines mutant embryos Abdominal-B protein expression is normal but incapable of promoting its normal functions: formation of the posterior spiracles and specification of an eighth abdominal denticle belt. These defects arise because in lines mutant embryos the Abdominal-B protein cannot activate its direct target empty spiracles or other downstream genes while it can function as a repressor of Ultrabithorax and abdominal-A. The lines gene seems to be required exclusively for Abdominal-B but not for the function of other Hox genes.

EPSD: a well-annotated data resource of protein phosphorylation sites in eukaryotes

2020 ◽  
Author(s):  
Shaofeng Lin ◽  
Chenwei Wang ◽  
Jiaqi Zhou ◽  
Ying Shi ◽  
Chen Ruan ◽  
...  
Keyword(s):  
Protein Phosphorylation ◽  
Phosphorylation Site ◽  
Model Organisms ◽  
Functional Domain ◽  
Phosphorylation Sites ◽  
Post Translational Modification ◽  
Structural Annotation ◽  
Data Resource ◽  
Protein Protein Interaction ◽  
Almost All

Abstract As an important post-translational modification (PTM), protein phosphorylation is involved in the regulation of almost all of biological processes in eukaryotes. Due to the rapid progress in mass spectrometry-based phosphoproteomics, a large number of phosphorylation sites (p-sites) have been characterized but remain to be curated. Here, we briefly summarized the current progresses in the development of data resources for the collection, curation, integration and annotation of p-sites in eukaryotic proteins. Also, we designed the eukaryotic phosphorylation site database (EPSD), which contained 1 616 804 experimentally identified p-sites in 209 326 phosphoproteins from 68 eukaryotic species. In EPSD, we not only collected 1 451 629 newly identified p-sites from high-throughput (HTP) phosphoproteomic studies, but also integrated known p-sites from 13 additional databases. Moreover, we carefully annotated the phosphoproteins and p-sites of eight model organisms by integrating the knowledge from 100 additional resources that covered 15 aspects, including phosphorylation regulator, genetic variation and mutation, functional annotation, structural annotation, physicochemical property, functional domain, disease-associated information, protein-protein interaction, drug-target relation, orthologous information, biological pathway, transcriptional regulator, mRNA expression, protein expression/proteomics and subcellular localization. We anticipate that the EPSD can serve as a useful resource for further analysis of eukaryotic phosphorylation. With a data volume of 14.1 GB, EPSD is free for all users at http://epsd.biocuckoo.cn/.

scholarly journals Acetylation of conserved DVL-1 lysines regulates its nuclear translocation and binding to gene promoters in triple-negative breast cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Monica Sharma ◽  
Deborah Molehin ◽  
Isabel Castro-Piedras ◽  
Edgar G. Martinez ◽  
Kevin Pruitt
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Translational Regulation ◽  
Cellular Localization ◽  
Triple Negative ◽  
Nuclear Translocation ◽  
Gene Promoters ◽  
Post Translational Modification ◽  
Protein Activity ◽  
Lysine Residues

Abstract Dishevelled (DVL) proteins are central mediators of the Wnt signalling pathway and are versatile regulators of several cellular processes, yet little is known about their post-translational regulation. Acetylation is a reversible post-translational modification (PTM) which regulates the function of several non-histone proteins involved in tumorigenesis. Since we previously demonstrated that lysine deacetylase, SIRT-1, regulates DVL protein levels and its function, we reasoned that DVL could potentially be a substrate for SIRT-1 mediated deacetylation. To further examine the potential role of multiple families of lysine deacetylases in the post-translational regulation of DVL, we screened for novel acetylation sites using liquid chromatography mass-spectrometry (LC-MS/MS) analysis. Herein, we report 12 DVL-1 lysine residues that show differential acetylation in response to changes in oxygen tension and deacetylase inhibition in triple-negative breast cancer (TNBC). PTMs are well documented to influence protein activity, and cellular localization. We also identify that acetylation of two key lysine residues, K69 and K285, present on the DIX and PDZ domains respectively, promote nuclear over cytoplasmic localization of DVL-1, and influences its promoter binding and regulation of genes implicated in cancer. Collectively, these findings for the first time, uncover acetylation as a novel layer of regulation of DVL-1 proteins.

A HOX complex, a repressor element and a 50 bp sequence confer regional specificity to a DPP-responsive enhancer

Development ◽  
2001 ◽  
Vol 128 (14) ◽  
pp. 2833-2845 ◽  
Author(s):  
Thomas Marty ◽  
M. Alessandra Vigano ◽  
Carlos Ribeiro ◽  
Ute Nussbaumer ◽  
Nicole C. Grieder ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cultured Cells ◽  
Cell Type ◽  
Response Element ◽  
Regional Specificity ◽  
A Cell ◽  
Cell Type Specific ◽  
Hox Protein ◽  
Repressor Element

A central theme during development and homeostasis is the generation of cell type-specific responses to the action of a limited number of extant signaling cascades triggered by extracellular ligands. The molecular mechanisms by which information from such signals are integrated in responding cells in a cell-type specific manner remain poorly understood. We have undertaken a detailed characterization of an enhancer that is regulated by DPP signaling and by the homeotic protein Labial and its partners, Extradenticle and Homothorax. The expression driven by this enhancer (lab550) and numerous deletions and point mutants thereof was studied in wild-type and mutant Drosophila embryos as well as in cultured cells. We find that the lab550 enhancer is composed of two elements, a Homeotic Response Element (HOMRE) and a DPP Response Element (DPPRE) that synergize. None of these two elements can reproduce the expression of lab550, either with regard to expression level or with regard to spatial restriction. The isolated DPPRE of lab550 responds extremely weakly to DPP. Interestingly, we found that the inducibility of this DPPRE is weak because it is tuned down by the action of a repressor element. This repressor element and an additional 50 bp element appear to be crucial for the cooperation of the HOMRE and the DPPRE, and might tightly link the DPP response to the homeotic input. The cooperation between the different elements of the enhancer leads to the segmentally restricted activity of lab550 in the endoderm and provides a mechanism to create specific responses to DPP signaling with the help of a HOX protein complex.

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