Journal articles on the topic 'Hox proteins'
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1
Shen, W. F., J. C. Montgomery, S. Rozenfeld, J. J. Moskow, H. J. Lawrence, A. M. Buchberg, and C. Largman. "AbdB-like Hox proteins stabilize DNA binding by the Meis1 homeodomain proteins." Molecular and Cellular Biology 17, no. 11 (November 1997): 6448–58. http://dx.doi.org/10.1128/mcb.17.11.6448.
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Recent studies show that Hox homeodomain proteins from paralog groups 1 to 10 gain DNA binding specificity and affinity through cooperative binding with the divergent homeodomain protein Pbx1. However, the AbdB-like Hox proteins from paralogs 11, 12, and 13 do not interact with Pbx1a, raising the possibility of different protein partners. The Meis1 homeobox gene has 44% identity to Pbx within the homeodomain and was identified as a common site of viral integration in myeloid leukemias arising in BXH-2 mice. These integrations result in constitutive activation of Meis1. Furthermore, the Hoxa-9 gene is frequently activated by viral integration in the same BXH-2 leukemias, suggesting a biological synergy between these two distinct classes of homeodomain proteins in causing malignant transformation. We now show that the Hoxa-9 protein physically interacts with Meis1 proteins by forming heterodimeric binding complexes on a DNA target containing a Meis1 site (TGACAG) and an AbdB-like Hox site (TTTTACGAC). Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b, while Hox proteins from other paralogs do not appear to interact with Meis1 proteins. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets.
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Mann, Richard S., and Markus Affolter. "Hox proteins meet more partners." Current Opinion in Genetics & Development 8, no. 4 (August 1998): 423–29. http://dx.doi.org/10.1016/s0959-437x(98)80113-5.
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Zhang, Jianxuan, Jae-Hung Shieh, Liren Liu, Magdalena Plasilova, Yue Zhang, Gianni Morrone, Malcolm A. S. Moore, and Pengbo Zhou. "Ubiquitin-Proteolytic Control of HOX Homeodomain Proteins." Blood 108, no. 11 (November 16, 2006): 1121. http://dx.doi.org/10.1182/blood.v108.11.1121.1121.
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Abstract The HOX homeodomain proteins are key regulators of hematopoiesis. HOX genes are expressed in primitive hematopoietic cells, and their prompt downregulation is associated with hematopoietic differentiation and maturation. Although transcriptional inactivation of HOX genes during hematopoietic differentiation has been established, little is known about the biochemical mechanisms underlying the subsequent removal of HOX proteins. We have previously shown that the CUL-4A ubiquitin ligase controls the stability of HOXA9 by promoting its ubiquitination and proteasome-dependent degradation. Interfering with CUL-4A biosynthesis results in altered HOXA9 protein levels, which is mirrored by the impairment of myeloid progenitor cells to undergo proper terminal differentiation into granulocytes. Here we show that additional HOX proteins are also subjected to CUL-4A-mediated ubiquitination and destruction. Consistently, the HOX homeodomain, which is highly conserved among all HOX proteins, is responsible for controlling their stability. Silencing of CUL-4A by RNA-mediated interference in human umbilical cord blood CD34+ cells significantly perturbs their self-renewal, expansion, and differentiation properties. These results reveal a novel regulatory mechanism of hematopoiesis by ubiquitin-dependent proteolysis. Recent studies on the biochemical mechanisms underlying HOX ubiquitination and by which leukemogenic HOX fusions evade CUL-4A-dependent degradation will be presented.
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Shen, Wei-fang, Keerthi Krishnan, H. J. Lawrence, and Corey Largman. "The HOX Homeodomain Proteins Block CBP Histone Acetyltransferase Activity." Molecular and Cellular Biology 21, no. 21 (November 1, 2001): 7509–22. http://dx.doi.org/10.1128/mcb.21.21.7509-7522.2001.
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ABSTRACT Despite the identification of PBC proteins as cofactors that provide DNA affinity and binding specificity for the HOX homeodomain proteins, HOX proteins do not demonstrate robust activity in transient-transcription assays and few authentic downstream targets have been identified for these putative transcription factors. During a search for additional cofactors, we established that each of the 14 HOX proteins tested, from 11 separate paralog groups, binds to CBP or p300. All six isolated homeodomain fragments tested bind to CBP, suggesting that the homeodomain is a common site of interaction. Surprisingly, CBP-p300 does not form DNA binding complexes with the HOX proteins but instead prevents their binding to DNA. The HOX proteins are not substrates for CBP histone acetyltransferase (HAT) but instead inhibit the activity of CBP in both in vitro and in vivo systems. These mutually inhibitory interactions are reflected by the inability of CBP to potentiate the low levels of gene activation induced by HOX proteins in a range of reporter assays. We propose two models for HOX protein function: (i) HOX proteins may function without CBP HAT to regulate transcription as cooperative DNA binding molecules with PBX, MEIS, or other cofactors, and (ii) the HOX proteins may inhibit CBP HAT activity and thus function as repressors of gene transcription.
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Martinou, Eirini, Giulia Falgari, Izhar Bagwan, and Angeliki M. Angelidi. "A Systematic Review on HOX Genes as Potential Biomarkers in Colorectal Cancer: An Emerging Role of HOXB9." International Journal of Molecular Sciences 22, no. 24 (December 14, 2021): 13429. http://dx.doi.org/10.3390/ijms222413429.
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Emerging evidence shows that Homeobox (HOX) genes are important in carcinogenesis, and their dysregulation has been linked with metastatic potential and poor prognosis. This review (PROSPERO-CRD42020190953) aims to systematically investigate the role of HOX genes as biomarkers in CRC and the impact of their modulation on tumour growth and progression. The MEDLINE, EMBASE, Web of Science and Cochrane databases were searched for eligible studies exploring two research questions: (a) the clinicopathological and prognostic significance of HOX dysregulation in patients with CRC and (b) the functional role of HOX genes in CRC progression. Twenty-five studies enrolling 3003 CRC patients, showed that aberrant expression of HOX proteins was significantly related to tumour depth, nodal invasion, distant metastases, advanced stage and poor prognosis. A post-hoc meta-analysis on HOXB9 showed that its overexpression was significantly associated with the presence of distant metastases (pooled OR 4.14, 95% CI 1.64–10.43, I2 = 0%, p = 0.003). Twenty-two preclinical studies showed that HOX proteins are crucially related to tumour growth and metastatic potential by affecting cell proliferation and altering the expression of epithelial-mesenchymal transition modulators. In conclusion, HOX proteins may play vital roles in CRC progression and are associated with overall survival. HOXB9 may be a critical transcription factor in CRC.
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Pellerin, I., C. Schnabel, K. M. Catron, and C. Abate. "Hox proteins have different affinities for a consensus DNA site that correlate with the positions of their genes on the hox cluster." Molecular and Cellular Biology 14, no. 7 (July 1994): 4532–45. http://dx.doi.org/10.1128/mcb.14.7.4532-4545.1994.
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The hox genes, members of a family of essential developmental regulators, have the intriguing property that their expression in the developing murine embryo is colinear with their chromosomal organization. Members of the hox gene family share a conserved DNA binding domain, termed the homeodomain, which mediates interactions of Hox proteins with DNA regulatory elements in the transcriptional control regions of target genes. In this study, we characterized the DNA binding properties of five representative members of the Hox family: HoxA5, HoxB4, HoxA7, HoxC8, and HoxB1. To facilitate a comparative analysis of their DNA binding properties, we produced the homeodomain regions of these Hox proteins in Escherichia coli and obtained highly purified polypeptides. We showed that these Hox proteins interact in vitro with a common consensus DNA site that contains the motif (C/G)TAATTG. We further showed that the Hox proteins recognize the consensus DNA site in vivo, as determined by their ability to activate transcription through this site in transient transfection assays. Although they interact optimally with the consensus DNA site, the Hox proteins exhibit subtle, but distinct, preferences for DNA sites that contain variations of the nucleotides within the consensus motif. In addition to their modest differences in DNA binding specificities, the Hox proteins also vary in their relative affinities for DNA. Intriguingly, their relative affinities correlate with the positions of their respective genes on the hox cluster. These findings suggest that subtle differences in DNA binding specificity combined with differences in DNA binding affinity constitute features of the "Hox code" that contribute to the selective functions of Hox proteins during murine embryogenesis.
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Pellerin, I., C. Schnabel, K. M. Catron, and C. Abate. "Hox proteins have different affinities for a consensus DNA site that correlate with the positions of their genes on the hox cluster." Molecular and Cellular Biology 14, no. 7 (July 1994): 4532–45. http://dx.doi.org/10.1128/mcb.14.7.4532.
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The hox genes, members of a family of essential developmental regulators, have the intriguing property that their expression in the developing murine embryo is colinear with their chromosomal organization. Members of the hox gene family share a conserved DNA binding domain, termed the homeodomain, which mediates interactions of Hox proteins with DNA regulatory elements in the transcriptional control regions of target genes. In this study, we characterized the DNA binding properties of five representative members of the Hox family: HoxA5, HoxB4, HoxA7, HoxC8, and HoxB1. To facilitate a comparative analysis of their DNA binding properties, we produced the homeodomain regions of these Hox proteins in Escherichia coli and obtained highly purified polypeptides. We showed that these Hox proteins interact in vitro with a common consensus DNA site that contains the motif (C/G)TAATTG. We further showed that the Hox proteins recognize the consensus DNA site in vivo, as determined by their ability to activate transcription through this site in transient transfection assays. Although they interact optimally with the consensus DNA site, the Hox proteins exhibit subtle, but distinct, preferences for DNA sites that contain variations of the nucleotides within the consensus motif. In addition to their modest differences in DNA binding specificities, the Hox proteins also vary in their relative affinities for DNA. Intriguingly, their relative affinities correlate with the positions of their respective genes on the hox cluster. These findings suggest that subtle differences in DNA binding specificity combined with differences in DNA binding affinity constitute features of the "Hox code" that contribute to the selective functions of Hox proteins during murine embryogenesis.
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Scott, Matthew P. "Hox proteins reach out round DNA." Nature 397, no. 6721 (February 1999): 649–51. http://dx.doi.org/10.1038/17685.
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Kyba, Michael. "Modulating the malignancy of Hox proteins." Blood 129, no. 3 (January 19, 2017): 269–70. http://dx.doi.org/10.1182/blood-2016-11-751909.
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Rinaldi, Lucrezia, Andrew J. Saurin, and Yacine Graba. "Fattening the perspective of Hox protein specificity through SLiMming." International Journal of Developmental Biology 62, no. 11-12 (2018): 755–66. http://dx.doi.org/10.1387/ijdb.180306yg.
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The functional identification and dissection of protein domains has been a successful approach towards the understanding of Hox protein specificity. However, only a few functional protein domains have been identified; this has been a major limitation in deciphering the molecular modalities of Hox protein action. We explore here, by in silico survey of short linear motifs (SLiMs) in Hox proteins, the contribution of SLiMs to Hox proteins, focusing on the mouse, chick and Drosophila Hox complement. Our findings reveal a widespread and uniform distribution of SLiMs along Hox protein sequences and identify the most apparent features of Hox associated SLiMs. While few motifs have been associated with Hox proteins so far, this work suggests that many more contribute to Hox protein functions. The potential and difficulties to apprehend the full contribution of SLiMs in controlling Hox protein functions are discussed.
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Galant, Ron, Christopher M. Walsh, and Sean B. Carroll. "Hox repression of a target gene: extradenticle-independent, additive action through multiple monomer binding sites." Development 129, no. 13 (July 1, 2002): 3115–26. http://dx.doi.org/10.1242/dev.129.13.3115.
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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.
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Beuchle, D., G. Struhl, and J. Muller. "Polycomb group proteins and heritable silencing of Drosophila Hox genes." Development 128, no. 6 (March 15, 2001): 993–1004. http://dx.doi.org/10.1242/dev.128.6.993.
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Early in Drosophila embryogenesis, transcriptional repressors encoded by Gap genes prevent the expression of particular combinations of Hox genes in each segment. During subsequent development, those Hox genes that were initially repressed in each segment remain off in all the descendent cells, even though the Gap repressors are no longer present. This phenomenon of heritable silencing depends on proteins of the Polycomb Group (PcG) and on cis-acting Polycomb response elements (PREs) in the Hox gene loci. We have removed individual PcG proteins from proliferating cells and then resupplied these proteins after a few or several cell generations. We show that most PcG proteins are required throughout development: when these proteins are removed, Hox genes become derepressed. However, we find that resupply of at least some PcG proteins can cause re-repression of Hox genes, provided that it occurs within a few cell generations of the loss of repression. These results suggest a functional distinction between transcriptional repression and heritable silencing: in at least some contexts, Hox genes can retain the capacity to be heritably silenced, despite being transcribed and replicated. We propose that silenced Hox genes bear a heritable, molecular mark that targets them for transcriptional repression. Some PcG proteins may be required to define and propagate this mark; others may function to repress the transcription of Hox genes that bear the mark.
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Paço, Ana, Simone Aparecida de Bessa Garcia, Joana Leitão Castro, Ana Rita Costa-Pinto, and Renata Freitas. "Roles of the HOX Proteins in Cancer Invasion and Metastasis." Cancers 13, no. 1 (December 22, 2020): 10. http://dx.doi.org/10.3390/cancers13010010.
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Invasion and metastasis correspond to the foremost cause of cancer-related death, and the molecular networks behind these two processes are extremely complex and dependent on the intra- and extracellular conditions along with the prime of the premetastatic niche. Currently, several studies suggest an association between the levels of HOX genes expression and cancer cell invasion and metastasis, which favour the formation of novel tumour masses. The deregulation of HOX genes by HMGA2/TET1 signalling and the regulatory effect of noncoding RNAs generated by the HOX loci can also promote invasion and metastasis, interfering with the expression of HOX genes or other genes relevant to these processes. In this review, we present five molecular mechanisms of HOX deregulation by which the HOX clusters products may affect invasion and metastatic processes in solid tumours.
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Bridoux, Laure, Françoise Gofflot, and René Rezsohazy. "HOX Protein Activity Regulation by Cellular Localization." Journal of Developmental Biology 9, no. 4 (December 7, 2021): 56. http://dx.doi.org/10.3390/jdb9040056.
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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.
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Chang, C. P., L. Brocchieri, W. F. Shen, C. Largman, and M. L. Cleary. "Pbx modulation of Hox homeodomain amino-terminal arms establishes different DNA-binding specificities across the Hox locus." Molecular and Cellular Biology 16, no. 4 (April 1996): 1734–45. http://dx.doi.org/10.1128/mcb.16.4.1734.
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Pbx cofactors are implicated to play important roles in modulating the DNA-binding properties of heterologous homeodomain proteins, including class I Hox proteins. To assess how Pbx proteins influence Hox DNA-binding specificity, we used a binding-site selection approach to determine high-affinity target sites recognized by various Pbx-Hox homeoprotein complexes. Pbx-Hox heterodimers preferred to bind a bipartite sequence 5'-ATGATTNATNN-3' consisting of two adjacent half sites in which the Pbx component of the heterodimer contacted the 5' half (ATGAT) and the Hox component contacted the more variable 3' half (TNATNN). Binding sites matching the consensus were also obtained for Pbx1 complexed with HoxA10, which lacks a hexapeptide but requires a conserved tryptophan-containing motif for cooperativity with Pbx. Interactions with Pbx were found to play an essential role in modulating Hox homeodomain amino-terminal arm contact with DNA in the core of the Hox half site such that heterodimers of different compositions could distinguish single nucleotide alterations in the Hox half site both in vitro and in cellular assays measuring transactivation. When complexed with Pbx, Hox proteins B1 through B9 and A10 showed stepwise differences in their preferences for nucleotides in the Hox half site core (TTAT to TGAT, 5' to 3') that correlated with the locations of their respective genes in the Hox cluster. These observations demonstrate previously undetected DNA-binding specificity for the amino-terminal arm of the Hox homeodomain and suggest that different binding activities of Pbx-Hox complexes are at least part of the position-specific activities of the Hox genes.
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Lu, Q., P. S. Knoepfler, J. Scheele, D. D. Wright, and M. P. Kamps. "Both Pbx1 and E2A-Pbx1 bind the DNA motif ATCAATCAA cooperatively with the products of multiple murine Hox genes, some of which are themselves oncogenes." Molecular and Cellular Biology 15, no. 7 (July 1995): 3786–95. http://dx.doi.org/10.1128/mcb.15.7.3786.
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E2A-PBX1 is the oncogene produced at the t(1;19) chromosomal breakpoint of pediatric pre-B-cell leukemia. Expression of E2A-Pbx1 induces fibroblast transformation and myeloid and T-cell leukemia in mice and arrests differentiation of granulocyte macrophage colony-stimulating factor-dependent myeloblasts in cultured marrow. Recently, the Drosophila melanogaster protein Exd, which is highly related to Pbx1, was shown to bind DNA cooperatively with the Drosophila homeodomain proteins Ubx and Abd-A. Here, we demonstrate that the normal Pbx1 homeodomain protein, as well as its oncogenic derivative, E2A-Pbx1, binds the DNA sequence ATCAATCAA cooperatively with the murine Hox-A5, Hox-B7, Hox-B8, and Hox-C8 homeodomain proteins, which are themselves known oncoproteins, as well as with the Hox-D4 homeodomain protein. Cooperative binding to ATCAATCAA required the homeodomain-dependent DNA-binding activities of both Pbx1 and the Hox partner. In cotransfection assays, Hox-B8 suppressed transactivation by E2A-Pbx1. These results suggest that (i) Pbx1 may participate in the normal regulation of Hox target gene transcription in vivo and therein contribute to aspects of anterior-posterior patterning and structural development in vertebrates, (ii) that E2A-Pbx1 could abrogate normal differentiation by altering the transcriptional regulation of Hox target genes in conjunction with Hox proteins, and (iii) that the oncogenic mechanism of certain Hox proteins may require their physical interaction with Pbx1 as a cooperating, DNA-binding partner.
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Carnesecchi, Julie, Pedro B. Pinto, and Ingrid Lohmann. "Hox transcription factors: an overview of multi-step regulators of gene expression." International Journal of Developmental Biology 62, no. 11-12 (2018): 723–32. http://dx.doi.org/10.1387/ijdb.180294il.
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Hox transcription factors (TFs) function as key determinants in the specification of cell fates during development. They do so by triggering entire morphogenetic cascades through the activation of specific target genes. In contrast to their fundamental role in development, the molecular mechanisms employed by Hox TFs are still poorly understood. In recent years, a new picture has emerged regarding the function of Hox proteins in gene regulation. Initial studies have primarily focused on understanding how Hox TFs recognize and bind specific enhancers to activate defined Hox targets. However, genome-wide studies on the interactions and dynamics of Hox proteins have revealed a more elaborate function of the Hox factors. It is now known that Hox proteins are involved in several steps of gene expression with potential regulatory functions in the modification of the chromatin landscape and its accessibility, recognition and activation of specific cis-regulatory modules, assembly and activation of promoter transcription complexes and mRNA processing. In the coming years, the characterization of the molecular activity of Hox TFs in these mechanisms will greatly contribute to our general understanding of Hox activity.
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Draime, Amandine, Laure Bridoux, Yacine Graba, and René Rezsohazy. "Post-translational modifications of HOX proteins, an underestimated issue." International Journal of Developmental Biology 62, no. 11-12 (2018): 733–44. http://dx.doi.org/10.1387/ijdb.180178rr.
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Post-translational modifications (PTMs) are important determinants which contribute to modulating the turn-over, intracellular localisation, molecular interactions and activity of most eukaryotic proteins. Such modifications and their consequences have been extensively examined for some proteins or classes of proteins. This is not the case for the HOX transcription factors which are crucial regulators of animal development. In this review, we provide a survey of the literature and data repositories pertaining to HOX-associated PTMs. This highlights that HOX proteins are also likely widely post-translationally modified, and defines HOX PTMs as an under-valued facet of their biology.
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Knoepfler, P. S., and M. P. Kamps. "The pentapeptide motif of Hox proteins is required for cooperative DNA binding with Pbx1, physically contacts Pbx1, and enhances DNA binding by Pbx1." Molecular and Cellular Biology 15, no. 10 (October 1995): 5811–19. http://dx.doi.org/10.1128/mcb.15.10.5811.
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The vertebrate Hox genes, which represent a subset of all homeobox genes, encode proteins that regulate anterior-posterior positional identity during embryogenesis and are cognates of the Drosophila homeodomain proteins encoded by genes composing the homeotic complex (HOM-C). Recently, we demonstrated that multiple Hox proteins bind DNA cooperatively with both Pbx1 and its oncogenic derivative, E2A-Pbx1. Here, we show that the highly conserved pentapeptide motif F/Y-P-W-M-R/K, which occurs in numerous Hox proteins and is positioned 8 to 50 amino acids N terminal to the homeodomain, is essential for cooperative DNA binding with Pbx1 and E2A-Pbx1. Point mutational analysis demonstrated that the tryptophan and methionine residues within the core of this motif were critical for cooperative DNA binding. A peptide containing the wild-type pentapeptide sequence, but not one in which phenylalanine was substituted for tryptophan, blocked the ability of Hox proteins to bind cooperatively with Pbx1 or E2A-Pbx1, suggesting that the pentapeptide itself provides at least one surface through which Hox proteins bind Pbx1. Furthermore, the same peptide, but not the mutant peptide, stimulated DNA binding by Pbx1, suggesting that interaction of Hox proteins with Pbx1 through the pentapeptide motif raises the DNA-binding ability of Pbx1.
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Gofflot, Françoise, and Benoit Lizen. "Emerging roles for HOX proteins in synaptogenesis." International Journal of Developmental Biology 62, no. 11-12 (2018): 807–18. http://dx.doi.org/10.1387/ijdb.180299fg.
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Neural circuit formation requires the intricate orchestration of multiple developmental events including cell fate specification, cell migration, axon guidance, dendritic growth, synaptic target selection, and synaptogenesis. The HOX proteins are well-known transcriptional regulators that control embryonic development. Investigations into their action in the vertebrate central nervous system have demonstrated pivotal roles in specifying neural subpopulations, but also in several successive steps required for the assembly of neuronal circuitry, such as neuron migration, axon growth and pathfinding and synaptic target selection. Several lines of evidence suggest that the HOX transcription factors could also regulate synaptogenesis processes even after the process of axonal and dendritic guidance has concluded. Here we will review the current data on HOX proteins in neural circuit formation in order to evaluate their potential roles in establishing neuronal connectivity with specific emphasis on synapse formation and maturation.
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Ryoo, H. D., T. Marty, F. Casares, M. Affolter, and R. S. Mann. "Regulation of Hox target genes by a DNA bound Homothorax/Hox/Extradenticle complex." Development 126, no. 22 (November 15, 1999): 5137–48. http://dx.doi.org/10.1242/dev.126.22.5137.
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To regulate their target genes, the Hox proteins of Drosophila often bind to DNA as heterodimers with the homeodomain protein Extradenticle (EXD). For EXD to bind DNA, it must be in the nucleus, and its nuclear localization requires a third homeodomain protein, Homothorax (HTH). Here we show that a conserved N-terminal domain of HTH directly binds to EXD in vitro, and is sufficient to induce the nuclear localization of EXD in vivo. However, mutating a key DNA binding residue in the HTH homeodomain abolishes many of its in vivo functions. HTH binds to DNA as part of a HTH/Hox/EXD trimeric complex, and we show that this complex is essential for the activation of a natural Hox target enhancer. Using a dominant negative form of HTH we provide evidence that similar complexes are important for several Hox- and exd-mediated functions in vivo. These data suggest that Hox proteins often function as part of a multiprotein complex, composed of HTH, Hox, and EXD proteins, bound to DNA.
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Chan, S. K., H. D. Ryoo, A. Gould, R. Krumlauf, and R. S. Mann. "Switching the in vivo specificity of a minimal Hox-responsive element." Development 124, no. 10 (May 15, 1997): 2007–14. http://dx.doi.org/10.1242/dev.124.10.2007.
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The homeodomain proteins encoded by the Hox complex genes do not bind DNA with high specificity. In vitro, Hox specificity can be increased by binding to DNA cooperatively with the homeodomain protein extradenticle or its vertebrate homologs, the pbx proteins (together, the PBC family). Here we show that a two basepair change in a Hox-PBC binding site switches the Hox-dependent expression pattern generated in vivo, from labial to Deformed. The change in vivo correlates with an altered Hox binding specificity in vitro. Further, we identify similar Deformed-PBC binding sites in the Deformed and Hoxb-4 genes and show that they generate Deformed or Hoxb-4 expression patterns in Drosophila and mouse embryos, respectively. These results suggest a model in which Hox-PBC binding sites play an instructive role in Hox specificity by promoting the formation of different Hox-PBC heterodimers in vivo. Thus, the choice of Hox partner, and therefore Hox target genes, depends on subtle differences between Hox-PBC binding sites.
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Laurent, Audrey, Rejane Bihan, Francis Omilli, Stephane Deschamps, and Isabelle Pellerin. "PBX proteins: much more than Hox cofactors." International Journal of Developmental Biology 52, no. 1 (2008): 9–20. http://dx.doi.org/10.1387/ijdb.072304al.
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Pavlopoulos, Anastasios, and Michalis Averof. "Developmental Evolution: Hox Proteins Ring the Changes." Current Biology 12, no. 8 (April 2002): R291—R293. http://dx.doi.org/10.1016/s0960-9822(02)00804-7.
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Vervoort, Michel. "Functional evolution of Hox proteins in arthropods." BioEssays 24, no. 9 (August 22, 2002): 775–79. http://dx.doi.org/10.1002/bies.10146.
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Hess, Jay L., Zhaohai Yang, Haoren Wang, Ya-Xiong Chen, Thomas A. Milne, Mary Ellen Martin, Robert K. Slany, and Xianxin Hua. "Interaction of MLL Amino Terminal Sequences with Menin Is Required for Transformation." Blood 106, no. 11 (November 16, 2005): 664. http://dx.doi.org/10.1182/blood.v106.11.664.664.
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Abstract Rearrangements of the mixed lineage leukemia gene MLL are associated with aggressive lymphoid and myeloid leukemias. The resulting MLL fusion proteins enforce high-level expression of HOX genes including HOX A7 and HOX A9 and the HOX cofactor MEIS1, which is pivotal for leukemogenesis. The mechanism by which this occurs and the relationship to normal MLL function is unknown. MLL and MLL fusion proteins bind with a similar distribution in hematopoietic cells at both promoters and coding sequences of target genes. Our studies suggest that a major mechanism of regulating MLL, which is expressed throughout hematopoiesis, is through modulating it’s binding to target promoters. MLL binds directly to the promoters and coding regions of HOX A7, HOX A9, and MEIS1 only in myeloblasts and not in neutrophils, indicating MLL is physically associated with genes only when they are actively transcribed. Expression of A cluster HOX loci and MEIS1 remains persistently elevated when MLL-ENL or dimerized MLL fusion proteins are expressed. Expression of either fusion protein is associated with increased binding of wild type MLL accompanied by increases in histone acetylation and histone H3 lysine 4, marks that are normally almost completely erased during myeloid differentiation. In addition MLL-ENL induces increased lysine 79 methylation. Both MLL and MLL fusion proteins interact with the tumor suppressor menin via sequences in the extreme amino terminus of MLL. In addition both proteins physically interact with RNA polymerase II, which shows abnormal pausing in the coding regions of HOX genes in Mll null cells. Genetic ablation of menin or expression of a dominant negative inhibitor of the MLL-menin interaction inhibits the growth of MLL fusion protein transformed cells. These findings suggest MLL fusion proteins act in concert with menin, MLL and other coactivators to deregulate HOX gene expression pivotal for transformation.
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Lu, Q., and M. P. Kamps. "Structural determinants within Pbx1 that mediate cooperative DNA binding with pentapeptide-containing Hox proteins: proposal for a model of a Pbx1-Hox-DNA complex." Molecular and Cellular Biology 16, no. 4 (April 1996): 1632–40. http://dx.doi.org/10.1128/mcb.16.4.1632.
Full textAbstract:
Genetic studies have identified a family of divergent homeodomain proteins, including the human protooncoprotein Pbx1 and its drosophila homolog extradenticle (Exd), which function as cofactors with a subset of Hox and HOM-C proteins, and are essential for specific target gene expression. Pbx1/Exd binds DNA elements cooperatively with a large subset of Hox/HOM-C proteins containing a conserved pentapeptide motif, usually YPWMR, located just N terminally to their homeodomains. The pentapeptide is essential for cooperative DNA binding with Pbx1. In this study, we identify structural determinants of Pbx1 that are required for cooperative DNA binding with the pentapeptide-containing Hox protein HoxA5. We demonstrate that the homeodomain of Pbx1 contains a surface that binds the pentapeptide motif and that the Pbx1 homeodomain is sufficient for cooperative DNA binding with a Hox protein. A sequence immediately C terminal to the Pbx1 homeodomain, which is highly conserved in Pbx2 and Pbx3 and predicted to form an alpha-helix, enhances monomeric DNA binding by Pbx1 and also contributes to maximal cooperativity with Hox proteins. Binding studies with chimeric HoxA5-Pbx1 fusion proteins suggest that the homeodomains of Pbx1 and HoxA5 are docked on the representative element, TTGATTGAT, in tandem, with Pbx1 recognizing the 5' TTGAT core motif and the Hox protein recognizing the 3' TGAT core. The proposed binding orientation permits Hox proteins to exhibit further binding specificity on the basis of the identity of the four residues 3' to their core binding motif.
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Viganò, Maria Alessandra, Giuliana Di Rocco, Vincenzo Zappavigna, and Fulvio Mavilio. "Definition of the Transcriptional Activation Domains of Three Human HOX Proteins Depends on the DNA-Binding Context." Molecular and Cellular Biology 18, no. 11 (November 1, 1998): 6201–12. http://dx.doi.org/10.1128/mcb.18.11.6201.
Full textAbstract:
ABSTRACT Hox proteins control developmental patterns and cell differentiation in vertebrates by acting as positive or negative regulators of still unidentified downstream target genes. The homeodomain and other small accessory sequences encode the DNA-protein and protein-protein interaction functions which ultimately dictate target recognition and functional specificity in vivo. The effector domains responsible for either positive or negative interactions with the cell transcriptional machinery are unknown for most Hox proteins, largely due to a lack of physiological targets on which to carry out functional analysis. We report the identification of the transcriptional activation domains of three human Hox proteins, HOXB1, HOXB3, and HOXD9, which interact in vivo with the autoregulatory and cross-regulatory enhancers of the murine Hoxb-1 and human HOXD9 genes. Activation domains have been defined both in a homologous context, i.e., within a HOX protein binding as a monomer or as a HOX-PBX heterodimer to the specific target, and in a heterologous context, after translocation to the yeast Gal4 DNA-binding domain. Transfection analysis indicates that activation domains can be identified in different regions of the three HOX proteins depending on the context in which they interact with the DNA target. These results suggest that Hox proteins may be multifunctional transcriptional regulators, interacting with different cofactors and/or components of the transcriptional machinery depending on the structure of their target regulatory elements.
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Salsi, Valentina, Silvia Ferrari, Roberta Ferraresi, Andrea Cossarizza, Alexis Grande, and Vincenzo Zappavigna. "HOXD13 Binds DNA Replication Origins To Promote Origin Licensing and Is Inhibited by Geminin." Molecular and Cellular Biology 29, no. 21 (August 24, 2009): 5775–88. http://dx.doi.org/10.1128/mcb.00509-09.
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ABSTRACT HOX DNA-binding proteins control patterning during development by regulating processes such as cell aggregation and proliferation. Recently, a possible involvement of HOX proteins in replication origin activity was suggested by results showing that a number of HOX proteins interact with the DNA replication licensing regulator geminin and bind a characterized human origin of replication. The functional significance of these observations, however, remained unclear. We show that HOXD13, HOXD11, and HOXA13 bind in vivo all characterized human replication origins tested. We furthermore show that HOXD13 interacts with the CDC6 loading factor, promotes pre-replication complex (pre-RC) proteins assembly at origins, and stimulates DNA synthesis in an in vivo replication assay. HOXD13 expression in cultured cells accelerates DNA synthesis initiation in correlation with the earlier pre-RC recruitment onto origins during G1 phase. Geminin, which interacts with HOXD13 as well, blocks HOXD13-mediated assembly of pre-RC proteins and inhibits HOXD13-induced DNA replication. Our results uncover a function for Hox proteins in the regulation of replication origin activity and reveal an unforeseen role for the inhibition of HOX protein activity by geminin in the context of replication origin licensing.
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Chang, C. P., Y. Jacobs, T. Nakamura, N. A. Jenkins, N. G. Copeland, and M. L. Cleary. "Meis proteins are major in vivo DNA binding partners for wild-type but not chimeric Pbx proteins." Molecular and Cellular Biology 17, no. 10 (October 1997): 5679–87. http://dx.doi.org/10.1128/mcb.17.10.5679.
Full textAbstract:
The Pbx1 and Meis1 proto-oncogenes code for divergent homeodomain proteins that are targets for oncogenic mutations in human and murine leukemias, respectively, and implicated by genetic analyses to functionally collaborate with Hox proteins during embryonic development and/or oncogenesis. Although Pbx proteins have been shown to dimerize with Hox proteins and modulate their DNA binding properties in vitro, the biochemical compositions of endogenous Pbx-containing complexes have not been determined. In the present study, we demonstrate that Pbx and Meis proteins form abundant complexes that comprise a major Pbx-containing DNA binding activity in nuclear extracts of cultured cells and mouse embryos. Pbx1 and Meis1 dimerize in solution and cooperatively bind bipartite DNA sequences consisting of directly adjacent Pbx and Meis half sites. Pbx1-Meis1 heterodimers display distinctive DNA binding specificities and cross-bind to a subset of Pbx-Hox sites, including those previously implicated as response elements for the execution of Pbx-dependent Hox programs in vivo. Chimeric oncoprotein E2a-Pbx1 is unable to bind DNA with Meis1, due to the deletion of amino-terminal Pbx1 sequences following fusion with E2a. We conclude that Meis proteins are preferred in vivo DNA binding partners for wild-type Pbx1, a relationship that is circumvented by its oncogenic counterpart E2a-Pbx1.
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Milne, Thomas A., Mary Ellen Martin, Robert K. Slany, and Jay L. Hess. "Leukemogenic MLL Fusion Proteins Promote MLL Association with HOX Loci Resulting in Persistent Expression." Blood 104, no. 11 (November 16, 2004): 386. http://dx.doi.org/10.1182/blood.v104.11.386.386.
Full textAbstract:
Abstract Rearrangements of the mixed lineage leukemia gene MLL are associated with aggressive lymphoid and myeloid leukemias. The resulting MLL fusion proteins enforce high-level expression of HOX genes including HOX A7 and HOX A9 and the HOX cofactor MEIS1, which is pivotal for leukemogenesis. The mechanism by which this occurs and the relationship to normal MLL function is unknown. To address this we performed a detailed study of where MLL and MLL fusion proteins bind at target genes in hematopoietic cells using quantitative chromatin immunoprecipitation (ChIP). In addition we characterized the histone modifications at the HOX A9 locus that occur with normal down modulation of HOX A9 expression during hematopoietic differentiation and how this is perturbed by induction of conditionally transforming MLL fusion proteins. These studies suggest that a major mechanism of regulating MLL, which is expressed throughout hematopoiesis, is through modulating it’s binding to target promoters. MLL binds directly to the promoters and coding regions of HOX A7, HOX A9, and MEIS1 only in myeloblasts and not in neutrophils, indicating MLL is physically associated with genes only when they are actively transcribed. Expression of A cluster HOX loci and MEIS1 is transiently increased by the addition of IL-3 but remains persistently elevated when MLL-ENL or dimerized MLL fusion proteins are expressed. Expression of either fusion protein is associated with increased binding of wild type MLL accompanied by increases in histone acetylation and histone H3 lysine 4 methylation, marks that are normally almost completely erased during myeloid differentiation. In addition MLL-ENL induces increased lysine 79 methylation. MLL extensively colocalizes with RNA polymerase II, which shows abnormal pausing in the coding regions of HOX genes in Mll null cells. These findings suggest MLL fusion proteins maintain expression of HOX genes critical for leukemogenesis through increased MLL binding resulting in both MLL dependent histone modifications and lysine 79 methylation and ultimately promotion of transcriptional elongation.
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Li, X., A. Veraksa, and W. McGinnis. "A sequence motif distinct from Hox binding sites controls the specificity of a Hox response element." Development 126, no. 24 (December 15, 1999): 5581–89. http://dx.doi.org/10.1242/dev.126.24.5581.
Full textAbstract:
Hox transcription factors, in combination with cofactors such as PBC proteins, provide diverse developmental fates to cells on the anteroposterior body axis of animal embryos. However, the mechanisms by which the different Hox proteins and their cofactors generate those diverse fates remain unclear. Recent findings have provided support for a model where the DNA binding sites that directly interact with Hox-PBC heterodimers determine which member of the Hox protein family occupies and thereby regulates a given target element. In the experiments reported here, we test the function of chimeric Hox response elements and, surprisingly, find evidence that runs counter to this view. A 21 bp cofactor binding sequence from an embryonic Deformed Hox response element, containing no Hox or Hox-PBC binding sites, was combined with single or multimeric sites that bind heterodimers of Labial-type Hox and PBC proteins. Normally, multimerized Labial-PBC binding sites are sufficient to trigger a Labial-specific activation response in either Drosophila or mouse embryos. Here we find that the 21 bp sequence element plays an important role in Deformed specificity, as it is capable of switching a Labial-PBC binding site/response element to a Deformed response element. Thus, cofactor binding sites that are separate and distinct from homeodomain binding sites can dictate the regulatory specificity of a Hox response element.
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Sánchez, M., P. A. Jennings, and C. Murre. "Conformational changes induced in Hoxb-8/Pbx-1 heterodimers in solution and upon interaction with specific DNA." Molecular and Cellular Biology 17, no. 9 (September 1997): 5369–76. http://dx.doi.org/10.1128/mcb.17.9.5369.
Full textAbstract:
Two classes of homeodomain proteins, Hox and Pbx gene products, have the ability to bind cooperatively to DNA. In Hox proteins, the homeodomain and a highly conserved hexapeptide are required for cooperative DNA binding. In Pbx, the homeodomain and a region immediately C terminal of the homeodomain are essential for cooperativity. Using fluorescence and circular dichroism spectroscopy, we demonstrated that Hox and Pbx proteins interact in the absence of DNA. The interaction in solution is accompanied by conformational changes. Furthermore, upon interaction with specific DNA, additional conformational changes are induced in the Pbx-1/Hoxb-8 heterodimer. These data indicate that prior to DNA binding, Hox-Pbx interaction in solution is accompanied by structural alterations. We propose that these conformational changes modulate the DNA binding properties of these proteins, ultimately resulting in cooperative DNA binding.
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Primon, Monika, Keith D. Hunter, Hardev S. Pandha, and Richard Morgan. "Kinase Regulation of HOX Transcription Factors." Cancers 11, no. 4 (April 10, 2019): 508. http://dx.doi.org/10.3390/cancers11040508.
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The HOX genes are a group of homeodomain-containing transcription factors that play important regulatory roles in early development, including the establishment of cell and tissue identity. HOX expression is generally reduced in adult cells but is frequently re-established as an early event in tumour formation and supports an oncogenic phenotype. HOX transcription factors are also involved in cell cycle regulation and DNA repair, along with normal adult physiological process including stem cell renewal. There have been extensive studies on the mechanism by which HOX proteins regulate transcription, with particular emphasis on their interaction with cofactors such as Pre-B-cell Leukaemia Homeobox (PBX) and Myeloid Ecotropic Viral Integration Site 1 (MEIS). However, significantly less is known of how the activity of HOX proteins is regulated. There is growing evidence that phosphorylation may play an important role in this context, and in this review, we draw together a number of important studies published over the last 20 years, and discuss the relevance of phosphorylation in the regulation and function of HOX proteins in development, evolution, cell cycle regulation, and cancer.
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Jacobs, Yakop, Catherine A. Schnabel, and Michael L. Cleary. "Trimeric Association of Hox and TALE Homeodomain Proteins Mediates Hoxb2 Hindbrain Enhancer Activity." Molecular and Cellular Biology 19, no. 7 (July 1, 1999): 5134–42. http://dx.doi.org/10.1128/mcb.19.7.5134.
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ABSTRACT Pbx/exd proteins modulate the DNA binding affinities and specificities of Hox proteins and contribute to the execution of Hox-dependent developmental programs in arthropods and vertebrates. Pbx proteins also stably heterodimerize and bind DNA with Meis and Pknox1-Prep1, additional members of the TALE (three-amino-acid loop extension) superclass of homeodomain proteins that function on common genetic pathways with a subset of Hox proteins. In this study, we demonstrated that Pbx and Meis bind DNA as heterotrimeric complexes with Hoxb1 on a genetically defined Hoxb2 enhancer, r4, that mediates the cross-regulatory transcriptional effects of Hoxb1 in vivo. The DNA binding specificity of the heterotrimeric complex for r4 is mediated by a Pbx-Hox site in conjunction with a distal Meis site, which we showed to be required for ternary complex formation and Meis-enhanced transcription. Formation of heterotrimeric complexes in which all three homeodomains bind their cognate DNA sites is topologically facilitated by the ability of Pbx and Meis to interact through their amino termini and bind DNA without stringent half-site orientation and spacing requirements. Furthermore, Meis site mutation in the Hoxb2 enhancer phenocopies Pbx-Hox site mutation to abrogate enhancer-directed expression of a reporter transgene in the murine embryonic hindbrain, demonstrating that DNA binding by all three proteins is required for trimer function in vivo. Our data provide in vitro and in vivo evidence for the combinatorial regulation of Hox and TALE protein functions that are mediated, in part, by their interdependent DNA binding activities as ternary complexes. As a consequence, Hoxb1 employs Pbx and Meis-related proteins, as a pair of essential cofactors in a higher-order molecular complex, to mediate its transcriptional effects on an endogenous Hox response element.
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Pineault, Nicolas, Carolina Abramovich, Hideaki Ohta, and R. Keith Humphries. "Differential and Common Leukemogenic Potentials of Multiple NUP98-Hox Fusion Proteins Alone or with Meis1." Molecular and Cellular Biology 24, no. 5 (March 1, 2004): 1907–17. http://dx.doi.org/10.1128/mcb.24.5.1907-1917.2004.
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ABSTRACT NUP98-Hox fusion genes are newly identified oncogenes isolated in myeloid leukemias. Intriguingly, only Abd-B Hox genes have been reported as fusion partners, indicating that they may have unique overlapping leukemogenic properties. To address this hypothesis, we engineered novel NUP98 fusions with Hox genes not previously identified as fusion partners: the Abd-B-like gene HOXA10 and two Antennepedia-like genes, HOXB3 and HOXB4. Notably, NUP98-HOXA10 and NUP98-HOXB3 but not NUP98-HOXB4 induced leukemia in a murine transplant model, which is consistent with the reported leukemogenic potential ability of HOXA10 and HOXB3 but not HOXB4. Thus, the ability of Hox genes to induce leukemia as NUP98 fusion partners, although apparently redundant for Abd-B-like activity, is not restricted to this group, but rather is determined by the intrinsic leukemogenic potential of the Hox partner. We also show that the potent leukemogenic activity of Abd-B-like Hox genes is correlated with their strong ability to block hematopoietic differentiation. Conversely, coexpression of the Hox cofactor Meis1 alleviated the requirement of a strong intrinsic Hox-transforming potential to induce leukemia. Our results support a model in which many if not all Hox genes can be leukemogenic and point to striking functional overlap not previously appreciated, presumably reflecting common regulated pathways.
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Peltenburg, L. T., and C. Murre. "Specific residues in the Pbx homeodomain differentially modulate the DNA-binding activity of Hox and Engrailed proteins." Development 124, no. 5 (March 1, 1997): 1089–98. http://dx.doi.org/10.1242/dev.124.5.1089.
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Two classes of homeodomain proteins, Hox and Engrailed, have been shown to act in concert with the atypical homeodomain proteins Pbx and extradenticle. We now show that specific residues located within the Pbx homeodomain are essential for cooperative DNA binding with Hox and Engrailed gene products. Within the N-terminal region of the Pbx homeodomain, we have identified a residue that is required for cooperative DNA binding with three Hox gene products but not for cooperativity with Engrailed-2 (En-2). Furthermore, there are similarities between heterodimeric interactions involving the yeast mating type proteins MATa1 and MATalpha2 and those that allow the formation of Pbx/Hox and Pbx/En-2 heterodimers. Specifically, residues located in the a1 homeodomain that were previously shown to form a hydrophobic pocket allowing the alpha2 C-terminal tail to bind, are also required for Pbx/Hox and Pbx/En-2 cooperativity. Furthermore, we show that three residues located in the turn between helix 1 and helix 2, characteristic of many atypical homeodomain proteins, are required for cooperative DNA binding involving both Hox and En-2. Replacement of the three residues located in the turn between helix 1 and helix 2 of the Pbx homeodomain with those of the atypical homeodomain proteins controlling cell fate in the basidiomycete Ustilago maydis, bE5 and bE6, allows cooperative DNA binding with three Hox members but abolishes interactions with En-2. The data suggest that the molecular mechanism of homeodomain protein interactions that control cell fate in Saccharomyces cerevisiae and in the basidiomycetes may well be conserved in part in multicellular organisms.
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Taniguchi, Yasushi. "Hox Transcription Factors: Modulators of Cell-Cell and Cell-Extracellular Matrix Adhesion." BioMed Research International 2014 (2014): 1–12. http://dx.doi.org/10.1155/2014/591374.
Full textAbstract:
Hoxgenes encode homeodomain-containing transcription factors that determine cell and tissue identities in the embryo during development.Hoxgenes are also expressed in various adult tissues and cancer cells. InDrosophila, expression of cell adhesion molecules, cadherins and integrins, is regulated by Hox proteins operating in hierarchical molecular pathways and plays a crucial role in segment-specific organogenesis. A number of studies using mammalian cultured cells have revealed that cell adhesion molecules responsible for cell-cell and cell-extracellular matrix interactions are downstream targets of Hox proteins. However, whether Hox transcription factors regulate expression of cell adhesion molecules during vertebrate development is still not fully understood. In this review, the potential roles Hox proteins play in cell adhesion and migration during vertebrate body patterning are discussed.
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Ghosh, Priyanjali, and Charles G. Sagerström. "Developing roles for Hox proteins in hindbrain gene regulatory networks." International Journal of Developmental Biology 62, no. 11-12 (2018): 767–74. http://dx.doi.org/10.1387/ijdb.180141cs.
Full textAbstract:
Hox proteins have long been known to function as transcriptional regulators during development of the vertebrate hindbrain. In particular, these factors are thought to play key roles in assigning distinct fates to the rhombomere segments arising in the embryonic hindbrain. However, it remains uncertain exactly how the Hox proteins fit into the regulatory networks controlling hindbrain formation. For instance, it is unclear if Hox proteins fulfill similar roles in different rhombomeres and if they are absolutely required for all aspects of each rhombomere fate. Recent advances in the discovery, characterization and functional analysis of hindbrain gene regulatory networks is now allowing us to revisit these types of questions. In this review we focus on recent data on the formation of caudal rhombomeres in vertebrates, with a specific focus on zebrafish, to derive an up-to-date view of the role for Hox proteins in the regulation of hindbrain development.
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Shanmugam, Kandavel, Nancy C. Green, Isabel Rambaldi, H. Uri Saragovi, and Mark S. Featherstone. "PBX and MEIS as Non-DNA-Binding Partners in Trimeric Complexes with HOX Proteins." Molecular and Cellular Biology 19, no. 11 (November 1, 1999): 7577–88. http://dx.doi.org/10.1128/mcb.19.11.7577.
Full textAbstract:
ABSTRACT HOX, PBX, and MEIS transcription factors bind DNA through a homeodomain. PBX proteins bind DNA cooperatively as heterodimers with MEIS family members and also with HOX proteins from paralog groups 1 to 10. MEIS proteins cooperatively bind DNA with ABD-B class HOX proteins of groups 9 and 10. Here, we examine aspects of dimeric and higher-order interactions between these three homeodomain classes. The most significant results can be summarized as follows. (i) Most of PBX N terminal to the homeodomain is required for efficient cooperative binding with HOXD4 and HOXD9. (ii) MEIS and PBX proteins form higher-order complexes on a heterodimeric binding site. (iii) Although MEIS does not cooperatively bind DNA with ANTP class HOX proteins, it does form a trimer as a non-DNA-binding partner with DNA-bound PBX-HOXD4. (iv) The N terminus of HOXD4 negatively regulates trimer formation. (v) MEIS forms a similar trimer with DNA-bound PBX-HOXD9. (vi) A related trimer (where MEIS is a non-DNA-binding partner) is formed on a transcriptional promoter within the cell. (vii) We observe an additional trimer class involving non-DNA-bound PBX and DNA-bound MEIS-HOXD9 or MEIS-HOXD10 heterodimers that is enhanced by mutation of the PBX homeodomain. (viii) In this latter trimer, PBX is likely to contact both MEIS and HOXD9/D10. (ix) The stability of DNA binding by all trimers is enhanced relative to the heterodimers. These findings suggest novel functions for PBX and MEIS in modulating the function of DNA-bound MEIS-HOX and PBX-HOX heterodimers, respectively.
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Joshi, R., L. Sun, and R. Mann. "Dissecting the functional specificities of two Hox proteins." Genes & Development 24, no. 14 (July 15, 2010): 1533–45. http://dx.doi.org/10.1101/gad.1936910.
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Ansari, Aseem Z., and Kimberly J. Peterson-Kaufman. "A Partner Evokes Latent Differences between Hox Proteins." Cell 147, no. 6 (December 2011): 1220–21. http://dx.doi.org/10.1016/j.cell.2011.11.046.
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Rossi, Alessandra, Karin J. Ferrari, Andrea Piunti, SriGanesh Jammula, Fulvio Chiacchiera, Luca Mazzarella, Andrea Scelfo, Pier Giuseppe Pelicci, and Diego Pasini. "Maintenance of leukemic cell identity by the activity of the Polycomb complex PRC1 in mice." Science Advances 2, no. 10 (October 2016): e1600972. http://dx.doi.org/10.1126/sciadv.1600972.
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Leukemia is a complex heterogeneous disease often driven by the expression of oncogenic fusion proteins with different molecular and biochemical properties. Whereas several fusion proteins induce leukemogenesis by activating Hox gene expression (Hox-activating fusions), others impinge on different pathways that do not involve the activation of Hox genes (non–Hox-activating fusions). It has been postulated that one of the main oncogenic properties of the HOXA9 transcription factor is its ability to control the expression of the p16/p19 tumor suppressor locus (Cdkn2a), thereby compensating Polycomb-mediated repression, which is dispensable for leukemias induced by Hox-activating fusions. We show, by genetically depleting the H2A ubiquitin ligase subunits of the Polycomb repressive complex 1 (PRC1), Ring1a and Ring1b, that Hoxa9 activation cannot repress Cdkn2a expression in the absence of PRC1 and its dependent deposition of H2AK119 monoubiquitination (H2AK119Ub). This demonstrates the essential role of PRC1 activity in supporting the oncogenic potential of Hox-activating fusion proteins. By combining genetic tools with genome-wide location and transcription analyses, we further show that PRC1 activity is required for the leukemogenic potential of both Hox-activating and non–Hox-activating fusions, thus preventing the differentiation of leukemic cells independently of the expression of the Cdkn2a locus. Overall, our results genetically demonstrate that PRC1 activity and the deposition of H2AK119Ub are critical factors that maintain the undifferentiated identity of cancer cells, positively sustaining the progression of different types of leukemia.
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Choe, Seong-Kyu, Nikolaos Vlachakis, and Charles G. Sagerström. "Meis family proteins are required for hindbrain development in the zebrafish." Development 129, no. 3 (February 1, 2002): 585–95. http://dx.doi.org/10.1242/dev.129.3.585.
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Meis homeodomain proteins function as Hox-cofactors by binding Pbx and Hox proteins to form multimeric complexes that control transcription of genes involved in development and differentiation. It is not known what role Meis proteins play in these complexes, nor is it clear which Hox functions require Meis proteins in vivo. We now show that a divergent Meis family member, Prep1, acts as a Hox co-factor in zebrafish. This suggests that all Meis family members have at least one shared function and that this function must be carried out by a conserved domain. We proceed to show that the Meinox domain, an N-terminal conserved domain shown to mediate Pbx binding, is sufficient to provide Meis activity to a Pbx/Hox complex. We find that this activity is separable from Pbx binding and resides within the M1 subdomain. This finding also presents a rational strategy for interfering with Meis activity in vivo. We accomplish this by expressing the Pbx4/Lzr N-terminus, which sequesters Meis proteins in the cytoplasm away from the nuclear transcription complexes. Sequestering Meis proteins in the cytoplasm leads to extensive loss of rhombomere (r) 3- and r4-specific gene expression, as well as defective rhombomere boundary formation in this region. These changes in gene expression correlate with impaired neuronal differentiation in r3 and r4, e.g. the loss of r3-specific nV branchiomotor neurons and r4-specific Mauthner neurons. We conclude that Meis family proteins are essential for the specification of r3 and r4 of the hindbrain.
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Castelli-Gair, J. "The lines gene of Drosophila is required for specific functions of the Abdominal-B HOX protein." Development 125, no. 7 (April 1, 1998): 1269–74. http://dx.doi.org/10.1242/dev.125.7.1269.
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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.
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Ozernyuk, Nikolay, and Dimitry Schepetov. "HOX-Gene Cluster Organization and Genome Duplications in Fishes and Mammals: Transcript Variant Distribution along the Anterior–Posterior Axis." International Journal of Molecular Sciences 23, no. 17 (September 1, 2022): 9990. http://dx.doi.org/10.3390/ijms23179990.
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Hox genes play a crucial role in morphogenesis, especially in anterior–posterior body axis patterning. The organization of Hox clusters in vertebrates is a result of several genome duplications: two rounds of duplication in the ancestors of all vertebrates and a third round that was specific for teleost fishes. Teleostei cluster structure has been significantly modified in the evolutionary processes by Hox gene losses and co-options, while mammals show no such tendency. In mammals, the Hox gene number in a single cluster is stable and generally large, and the numbers are similar to those in the Chondrichthyes. Hox gene alternative splicing activity slightly differs between fishes and mammals. Fishes and mammals have differences in their known alternative splicing activity for Hox gene distribution along the anterior–posterior body axis. The analyzed fish groups—the Coelacanthiformes, Chondrichthyes, and Teleostei—all have higher known alternative mRNA numbers from the anterior and posterior regions, whereas mammals have a more uniform Hox transcript distribution along this axis. In fishes, most Hox transcripts produce functioning proteins, whereas mammals have significantly more known transcripts that do not produce functioning proteins.
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Alper, Scott, and Cynthia Kenyon. "The zinc finger protein REF-2 functions with the Hox genes to inhibit cell fusion in the ventral epidermis of C. elegans." Development 129, no. 14 (July 15, 2002): 3335–48. http://dx.doi.org/10.1242/dev.129.14.3335.
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During larval development in C. elegans, some of the cells of the ventral epidermis, the Pn.p cells, fuse with the growing epidermal syncytium hyp7. The pattern of these cell fusions is regulated in a complex, sexually dimorphic manner. It is essential that some Pn.p cells remain unfused in order for some sex-specific mating structures to be generated. The pattern of Pn.p cell fusion is regulated combinatorially by two genes of the C. elegans Hox gene cluster: lin-39 and mab-5. Some of the complexity in the Pn.p cell fusion pattern arises because these two Hox proteins can regulate each other’s activities. We describe a zinc-finger transcription factor, REF-2, that is required for the Pn.p cells to be generated and to remain unfused. REF-2 functions with the Hox proteins to prevent Pn.p cell fusion. ref-2 may also be a transcriptional target of the Hox proteins.
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Remacle, Sophie, Leïla Abbas, Olivier De Backer, Nathalie Pacico, Anthony Gavalas, Françoise Gofflot, Jacques J. Picard, and René Rezsöhazy. "Loss of Function but No Gain of Function Caused by Amino Acid Substitutions in the Hexapeptide of Hoxa1 In Vivo." Molecular and Cellular Biology 24, no. 19 (October 1, 2004): 8567–75. http://dx.doi.org/10.1128/mcb.24.19.8567-8575.2004.
Full textAbstract:
ABSTRACT Homeodomain containing transcription factors of the Hox family play critical roles in patterning the anteroposterior embryonic body axis, as well as in controlling several steps of organogenesis. Several Hox proteins have been shown to cooperate with members of the Pbx family for the recognition and activation of identified target enhancers. Hox proteins contact Pbx via a conserved hexapeptide motif. Previous biochemical studies provided evidence that critical amino acid substitutions in the hexapeptide sequence of Hoxa1 abolish its interaction with Pbx. As a result, these substitutions also abolish Hoxa1 activity on known target enhancers in cellular models, suggesting that Hoxa1 activity relies on its capacity to interact with Pbx. Here, we show that mice with mutations in the Hoxa1 hexapeptide display hindbrain, cranial nerve, and skeletal defects highly reminiscent of those reported for the Hoxa1 loss of function. Since similar hexapeptide mutations in the mouse Hoxb8 and the Drosophila AbdA proteins result in activity modulation and gain of function, our data demonstrate that the functional importance of the hexapeptide in vivo differs according to the Hox proteins.
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Ch'ng, Q., and C. Kenyon. "egl-27 generates anteroposterior patterns of cell fusion in C. elegans by regulating Hox gene expression and Hox protein function." Development 126, no. 15 (August 1, 1999): 3303–12. http://dx.doi.org/10.1242/dev.126.15.3303.
Full textAbstract:
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.
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De Kumar, Bony, and Diane C. Darland. "The Hox protein conundrum: The “specifics” of DNA binding for Hox proteins and their partners." Developmental Biology 477 (September 2021): 284–92. http://dx.doi.org/10.1016/j.ydbio.2021.06.002.
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