1,721,006 research outputs found
Special issue on HOX genes in development
Full text linkThis Special Issue of Journal of Developmental Biology (JDB) covers an indeed very "special" (at least to me) family of highly evolutionarily conserved genes, the Hox genes.[...]
Developed to cull: how a master control gene of development turned into a regulator of innate immune homeostasis
Full text linkA striking novel role for the Caudal "master control" gene of development in the regulation of innate immune functions in insects has emerged. A recent study now adds further insight into the function of this homeobox gene in the maintenance of the immune homeostasis that is required to preserve the normal commensal community within the Drosophila gut. These results point to a possible more widespread co-option of developmental regulatory genes during evolution to add tissue- and/or organ-specific regulatory plasticity to innate immune systems
Corrigendum: ‘Building a perfect body’: Control of vertebrate organogenesis by PBX-dependent regulatory networks (Genes & Development 33: 258–275 (2019)
No full textIn the above-mentioned article, the funding source NNF17CC0027852 to Elisabetta Ferretti was missing from Acknowledgments and has been added as follows: “This work was supported by The Novo Nordisk Foundation Center for Stem Cell Biology (NNF17CC0027852 to E.F.).”
Specificity of HOX protein function depends on DNA-protein and protein- protein interactions, both mediated by the homeo domain
Full text linkTranscription of human HOX gene promoters in cultured cells is positively and negatively regulated by HOX proteins interacting with specific target sequences. The human HOXD9 protein activates transcription of the HOXD9 promoter by interacting with the HCR sequence and is antagonized by the HOXD8 protein. HOXD8 is not intrinsically a repressor, since it can activate transcription on different targets. Complete or partial HOXD8/HOXD9 homeo domain swapping indicates that the ability to recognize, and activate transcription from, the HCR target in vivo depends on the amino terminus and helix 1 of the homeo domain. The inhibitory activity of HOXD8 is not affected by deletion of the homeo domain helix 2/3 region, whereas it requires the amino terminus/helix 1 region and an additional, effector domain located at the protein amino-terminal end. This activity is therefore DNA-binding independent, and possibly mediated by protein-protein interactions. Affinity chromatography experiments show that the homeo domain amino terminus/helix 1 region is able to mediate direct interactions between HOX proteins in solution. These data indicate that specificity of HOX protein function in vivo depends on both DNA-protein and protein-protein interactions, mediated by the same sub region of the homeo domain
Inhibition of retinoic acid-induced activation of 3' human HOXB genes by antisense oligonucleotides affects sequential activation of genes located upstream in the four HOX clusters
No full textMost homeobox genes belonging to the Hox family are sequentially activated in embryonal carcinoma cells upon treatment with retinoic acid. Genes located at the 3' end of each one of the four Hox clusters are activated progressively later. This activation has been extensively studied for human HOX genes in the NT2/D1 cell line and shown to take place at the transcriptional level. To understand the molecular mechanisms of sequential HOX gene activation in these cells, we tried to modulate the expression of 3' HOX genes through the use of antisense oligonucleotides added to the culture medium. We chose the HOXB locus. A 5- to 15-fold reduction of the expression of HOXB1 and HOXB3 was sufficient to produce a significant inhibition of the activation of the upstream HOXB genes, as well as of their paralogs in the HOXA, HOXC, and HOXD clusters. Conversely, no effect was detectable on downstream HOX genes. The extent of this inhibition increased for progressively more-5' genes. The stability of the corresponding mRNAs appeared to be unaffected, supporting the idea that the observed effect might be mediated at the transcriptional level. These data suggest a cascade model of progressive activation of Hox genes, with a 3'-to-5' polarity
A novel homeo-domain protein, prep 1, forms a regulatory complex with pbx proteins in vivo
No full textExpression of the human urokinase (uPA) gene is regulated by an enhancer containing a combined PEA3/AP-1 site and an AP-1 site, spaced 72bp apart. These two sites have been shown to synergistically cooperate in both basal level and PMA induced activity of the enhancer, dependent on an element, the co-operation mediator (COM) element, positioned between the two sites, and which bind several different nuclear factors. uPA Enhancer Factor 3 (UEF3) has been identified in various cell lines binding specifically to a site within the COM element and in addition, binds to similar regulating motifs found in various other promoters, showing similar organization and activity as the uPA enhancer. We have purified UEF3 from HeLa cell nuclei by standard chromatography. Purification data show that UEF3 is a complex formed by three polypeptides, p64, p50 and p40. Overall, the data further suggest that UEF3 is a heterodimer consiting of p64 complexed with either p50 orp40. We have cloned the cDNA p64, which encodes for a novel protein, termed Prepl, containing a homeodomain similar to those found in mammalian PBX and Drosophila Extradenticle (exd) homeo domain proteins and in yeast Mat2a protein. We find that Prepl exist as a stable complex with Pbx proteins in vivo and that this complex can be made in vitro reconstituting UEF3 activity. Pbx are proteins known to functionally interact with Hox proteins during development. Both its structure and its way of interacting with Pbx, show that Prepl is different from Hox proteins, and our data point to a novel regulatory role for Pbx/Prepl complexes proteins independent on Hox
Prep1, a novel functional partner of Pbx proteins
No full textThe human transcription factor, UEF3, is important in regulating the activity of the urokinase plasminogen activator (uPA) gene enhancer. The UEF3 DNA target site is a regulatory element in the promoters of several growth factor and protease genes. We reported previously that purified UEF3 is a complex of several subunits. In this paper we report the cloning of the cDNA of one of the subunits which encodes for a novel human homeodomain protein, which we have termed Prep1. The Prep1 homeodomain belongs to the TALE class of homeodomains, is most closely related to those of the TGIF and Meis1 proteins, and like these, recognizes a TGACAG motif. We further identify the other UEF3 subunit as a member of the Pbx protein family. Unlike other proteins known to interact with Pbx, Prep1 forms a stable complex with Pbx independent of DNA binding. Heterodimerization of Prep1 and Pbx results in a strong DNA binding affinity towards the TGACAG target site of the uPA promoter. Overall, these data indicate that Prep1 is a stable intracellular partner of Pbx in vivo
The novel homeoprotein Prep1 modulates Pbx-Hox protein cooperativity
Full text linkThe products of the mammalian Pbx and Drosophila exd genes are able to interact with Hox proteins specifically and to increase their DNA binding affinity and selectivity. In the accompanying paper we show that Pbx proteins exist as stable heterodimers with a novel homeodomain protein, Prep1. Here we show that Prep1-Pbx interaction presents novel structural features: it is independent of DNA binding and of the integrity of their respective homeodomains, and requires sequences in the N-terminal portions of both proteins. The Prep1-Pbx protein-protein interaction is essential for DNA-binding activity, Prep1-Pbx complexes are present in early mouse embryos at a time when Pbx is also interacting with Hox proteins. The use of different interaction surfaces could allow Pbx to interact with Prep1 and Hox proteins simultaneously. Indeed, we observe the formation of a ternary Prep1-Pbx1-HOXB1 complex on a HOXB1-responsive target in vitro. Interaction with Prep1 enhances the ability of the HOXB1-Pbx1 complex to activate transcription in a cooperative fashion from the same target. Our data suggest that Prep1 is an additional component in the transcriptional regulation by Hox proteins
HMG1 interacts with HOX proteins and enhances their DNA binding and transcriptional activation
No full textHigh mobility group protein 1 (HMG1) is a non-histone, chromatin-associated nuclear protein with a proposed role in the regulation of eukaryotic gene expression. We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein. Functional interaction between HMG1 and HOXD9 is dependent on the DNA binding activity of the homeodomain, and requires the HOXD9 transcriptional activation domain. HMG1 enhances activation by HOXD9, but not by HOXD8, of the HOXD9-controlled element. Specific target recognition and functional interaction with HMG1 can be transferred to HOXD8 by homeodomain swapping. We propose that HMG1-like proteins might be general co-factors in HOX-mediated transcriptional activation, which facilitate access of HOX proteins to specific DNA targets, and/or introduce architectural constraints in the assembly of HOX-containing transcriptional complexes
‘Building a perfect body’: Control of vertebrate organogenesis by PBX-dependent regulatory networks
Full text linkPbx genes encode transcription factors that belong to the TALE (three-amino-acid loop extension) superclass of homeodomain proteins. We have witnessed a surge in information about the roles of this gene family as leading actors in the transcriptional control of development. PBX proteins represent a clear example of how transcription factors can regulate developmental processes by combinatorial properties, acting within multimeric complexes to implement activation or repression of transcription depending on their interaction partners. Here, we revisit long-emphasized functions of PBX transcription factors as cofactors for HOX proteins, major architects of the body plan. We further discuss new knowledge on roles of PBX proteins in different developmental contexts as upstream regulators of Hox genes—as factors that interact with non-HOX proteins and can work independently of HOX—as well as potential pioneer factors. Committed to building a perfect body, PBX proteins govern regulatory networks that direct essential morphogenetic processes and organogenesis in vertebrate development. Perturbations of PBX-dependent networks can cause human congenital disease and cancer
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