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Belpaire M, Taminiau A, Geerts D, Rezsohazy R. HOXA1, a breast cancer oncogene. Biochim Biophys Acta Rev Cancer 2022; 1877:188747. [PMID: 35675857 DOI: 10.1016/j.bbcan.2022.188747] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 04/27/2022] [Accepted: 06/01/2022] [Indexed: 12/24/2022]
Abstract
More than 25 years ago, the first literature records mentioned HOXA1 expression in human breast cancer. A few years later, HOXA1 was confirmed as a proper oncogene in mammary tissue. In the following two decades, molecular data about the mode of action of the HOXA1 protein, the factors contributing to activate and maintain HOXA1 gene expression and the identity of its target genes have accumulated and provide a wider view on the association of this transcription factor to breast oncogenesis. Large-scale transcriptomic data gathered from wide cohorts of patients further allowed refining the relationship between breast cancer type and HOXA1 expression. Several recent reports have reviewed the connection between cancer hallmarks and the biology of HOX genes in general. Here we take HOXA1 as a paradigm and propose an extensive overview of the molecular data centered on this oncoprotein, from what its expression modulators, to the interactors contributing to its oncogenic activities, and to the pathways and genes it controls. The data converge to an intricate picture that answers questions on the multi-modality of its oncogene activities, point towards better understanding of breast cancer aetiology and thereby provides an appraisal for treatment opportunities.
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Affiliation(s)
- Magali Belpaire
- Animal Molecular and Cellular Biology Group (AMCB), Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain, Louvain-la-Neuve, Belgium
| | - Arnaud Taminiau
- Animal Molecular and Cellular Biology Group (AMCB), Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain, Louvain-la-Neuve, Belgium
| | - Dirk Geerts
- Heart Failure Research Center, Amsterdam University Medical Center (AMC), Universiteit van Amsterdam, Amsterdam, the Netherlands.
| | - René Rezsohazy
- Animal Molecular and Cellular Biology Group (AMCB), Louvain Institute of Biomolecular Science and Technology (LIBST), UCLouvain, Louvain-la-Neuve, Belgium.
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2
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Carnesecchi J, Boumpas P, van Nierop Y Sanchez P, Domsch K, Pinto HD, Borges Pinto P, Lohmann I. The Hox transcription factor Ultrabithorax binds RNA and regulates co-transcriptional splicing through an interplay with RNA polymerase II. Nucleic Acids Res 2021; 50:763-783. [PMID: 34931250 PMCID: PMC8789087 DOI: 10.1093/nar/gkab1250] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 12/01/2021] [Accepted: 12/07/2021] [Indexed: 11/13/2022] Open
Abstract
Transcription factors (TFs) play a pivotal role in cell fate decision by coordinating gene expression programs. Although most TFs act at the DNA layer, few TFs bind RNA and modulate splicing. Yet, the mechanistic cues underlying TFs activity in splicing remain elusive. Focusing on the Drosophila Hox TF Ultrabithorax (Ubx), our work shed light on a novel layer of Ubx function at the RNA level. Transcriptome and genome-wide binding profiles in embryonic mesoderm and Drosophila cells indicate that Ubx regulates mRNA expression and splicing to promote distinct outcomes in defined cellular contexts. Our results demonstrate a new RNA-binding ability of Ubx. We find that the N51 amino acid of the DNA-binding Homeodomain is non-essential for RNA interaction in vitro, but is required for RNA interaction in vivo and Ubx splicing activity. Moreover, mutation of the N51 amino acid weakens the interaction between Ubx and active RNA Polymerase II (Pol II). Our results reveal that Ubx regulates elongation-coupled splicing, which could be coordinated by a dynamic interplay with active Pol II on chromatin. Overall, our work uncovered a novel role of the Hox TFs at the mRNA regulatory layer. This could be an essential function for other classes of TFs to control cell diversity.
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Affiliation(s)
- Julie Carnesecchi
- Heidelberg University, Centre for Organismal Studies (COS) Heidelberg, Department of Developmental Biology, Heidelberg, Germany.,Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, CNRS UMR5242, Ecole Normale Supérieure de Lyon, Lyon, France
| | - Panagiotis Boumpas
- Heidelberg University, Centre for Organismal Studies (COS) Heidelberg, Department of Developmental Biology, Heidelberg, Germany
| | - Patrick van Nierop Y Sanchez
- Heidelberg University, Centre for Organismal Studies (COS) Heidelberg, Department of Developmental Biology, Heidelberg, Germany
| | - Katrin Domsch
- Heidelberg University, Centre for Organismal Studies (COS) Heidelberg, Department of Developmental Biology, Heidelberg, Germany.,Friedrich-Alexander-University Erlangen-Nürnberg, Department Biology, Division of Developmental Biology, Erlangen, Germany
| | - Hugo Daniel Pinto
- Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA
| | - Pedro Borges Pinto
- Heidelberg University, Centre for Organismal Studies (COS) Heidelberg, Department of Developmental Biology, Heidelberg, Germany.,Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, CNRS UMR5242, Ecole Normale Supérieure de Lyon, Lyon, France
| | - Ingrid Lohmann
- Heidelberg University, Centre for Organismal Studies (COS) Heidelberg, Department of Developmental Biology, Heidelberg, Germany
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3
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Bridoux L, Gofflot F, Rezsohazy R. HOX Protein Activity Regulation by Cellular Localization. J Dev Biol 2021; 9:jdb9040056. [PMID: 34940503 PMCID: PMC8707151 DOI: 10.3390/jdb9040056] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/29/2021] [Accepted: 12/02/2021] [Indexed: 12/18/2022] Open
Abstract
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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Planques A, Oliveira Moreira V, Benacom D, Bernard C, Jourdren L, Blugeon C, Dingli F, Masson V, Loew D, Prochiantz A, Di Nardo AA. OTX2 Homeoprotein Functions in Adult Choroid Plexus. Int J Mol Sci 2021; 22:8951. [PMID: 34445655 PMCID: PMC8396604 DOI: 10.3390/ijms22168951] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/12/2021] [Accepted: 08/17/2021] [Indexed: 01/18/2023] Open
Abstract
The choroid plexus is an important blood barrier that secretes cerebrospinal fluid, which essential for embryonic brain development and adult brain homeostasis. The OTX2 homeoprotein is a transcription factor that is critical for choroid plexus development and remains highly expressed in adult choroid plexus. Through RNA sequencing analyses of constitutive and conditional knockdown adult mouse models, we reveal putative functional roles for OTX2 in adult choroid plexus function, including cell signaling and adhesion, and show that OTX2 regulates the expression of factors that are secreted into the cerebrospinal fluid, notably transthyretin. We also show that Otx2 expression impacts choroid plexus immune and stress responses, and affects splicing, leading to changes in the mRNA isoforms of proteins that are implicated in the oxidative stress response and DNA repair. Through mass spectrometry analysis of OTX2 protein partners in the choroid plexus, and in known non-cell-autonomous target regions, such as the visual cortex and subventricular zone, we identify putative targets that are involved in cell adhesion, chromatin structure, and RNA processing. Thus, OTX2 retains important roles for regulating choroid plexus function and brain homeostasis throughout life.
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Affiliation(s)
- Anabelle Planques
- Centre for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS UMR7241, INSERM U1050, Labex MemoLife, PSL University, 75005 Paris, France; (A.P.); (V.O.M.); (D.B.); (C.B.); (A.P.)
| | - Vanessa Oliveira Moreira
- Centre for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS UMR7241, INSERM U1050, Labex MemoLife, PSL University, 75005 Paris, France; (A.P.); (V.O.M.); (D.B.); (C.B.); (A.P.)
| | - David Benacom
- Centre for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS UMR7241, INSERM U1050, Labex MemoLife, PSL University, 75005 Paris, France; (A.P.); (V.O.M.); (D.B.); (C.B.); (A.P.)
| | - Clémence Bernard
- Centre for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS UMR7241, INSERM U1050, Labex MemoLife, PSL University, 75005 Paris, France; (A.P.); (V.O.M.); (D.B.); (C.B.); (A.P.)
| | - Laurent Jourdren
- Genomics Core Facility, Institut de Biologie de l’ENS (IBENS), Département de Biologie, École Normale Supérieure, CNRS, INSERM, PSL University, 75005 Paris, France; (L.J.); (C.B.)
| | - Corinne Blugeon
- Genomics Core Facility, Institut de Biologie de l’ENS (IBENS), Département de Biologie, École Normale Supérieure, CNRS, INSERM, PSL University, 75005 Paris, France; (L.J.); (C.B.)
| | - Florent Dingli
- Laboratoire de Spectrométrie de Masse Protéomique, Centre de Recherche, Institut Curie, CEDEX 05, 75248 Paris, France; (F.D.); (V.M.); (D.L.)
| | - Vanessa Masson
- Laboratoire de Spectrométrie de Masse Protéomique, Centre de Recherche, Institut Curie, CEDEX 05, 75248 Paris, France; (F.D.); (V.M.); (D.L.)
| | - Damarys Loew
- Laboratoire de Spectrométrie de Masse Protéomique, Centre de Recherche, Institut Curie, CEDEX 05, 75248 Paris, France; (F.D.); (V.M.); (D.L.)
| | - Alain Prochiantz
- Centre for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS UMR7241, INSERM U1050, Labex MemoLife, PSL University, 75005 Paris, France; (A.P.); (V.O.M.); (D.B.); (C.B.); (A.P.)
- Institute of Neurosciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China
| | - Ariel A. Di Nardo
- Centre for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS UMR7241, INSERM U1050, Labex MemoLife, PSL University, 75005 Paris, France; (A.P.); (V.O.M.); (D.B.); (C.B.); (A.P.)
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Abstract
Knowledge of the role of HOX proteins in cancer has been steadily accumulating in the last 25 years. They are encoded by 39 HOX genes arranged in 4 distinct clusters, and have unique and redundant function in all types of cancers. Many HOX genes behave as oncogenic transcriptional factors regulating multiple pathways that are critical to malignant progression in a variety of tumors. Some HOX proteins have dual roles that are tumor-site specific, displaying both oncogenic and tumor suppressor function. The focus of this review is on how HOX proteins contribute to growth or suppression of metastasis. The review will cover HOX protein function in the critical aspects of epithelial-mesenchymal transition, in cancer stem cell sustenance and in therapy resistance, manifested as distant metastasis. The emerging role of adiposity in both initiation and progression of metastasis is described. Defining the role of HOX genes in the metastatic process has identified candidates for targeted cancer therapies that may combat the metastatic process. We will discuss potential therapeutic opportunities, particularly in pathways influenced by HOX proteins.
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de Bessa Garcia SA, Araújo M, Pereira T, Mouta J, Freitas R. HOX genes function in Breast Cancer development. Biochim Biophys Acta Rev Cancer 2020; 1873:188358. [PMID: 32147544 DOI: 10.1016/j.bbcan.2020.188358] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 03/03/2020] [Accepted: 03/03/2020] [Indexed: 02/07/2023]
Abstract
Breast cancer develops in the mammary glands during mammalian adulthood and is considered the second most common type of human carcinoma and the most incident and mortal in the female population. In contrast to other human structures, the female mammary glands continue to develop after birth, undergoing various modifications during pregnancy, lactation and involution under the regulation of hormones and transcription factors, including those encoded by the HOX clusters (A, B, C, and D). Interestingly, HOX gene deregulation is often associated to breast cancer development. Within the HOXB cluster, 8 out of the 10 genes present altered expression levels in breast cancer with an impact in its aggressiveness and resistance to hormone therapy, which highlights the importance of HOXB genes as potential therapeutic targets used to overcome the limitations of tamoxifen-resistant cancer treatments. Here, we review the current state of knowledge on the role of HOX genes in breast cancer, specially focus on HOXB, discussing the causes and consequences of HOXB gene deregulation and their relevance as prognostic factors and therapeutic targets.
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Affiliation(s)
- Simone Aparecida de Bessa Garcia
- IBMC- Institute for Molecular and Cell Biology, I3S- Institute for Innovation and Health Research, Universidade do Porto, Portugal
| | - Mafalda Araújo
- IBMC- Institute for Molecular and Cell Biology, I3S- Institute for Innovation and Health Research, Universidade do Porto, Portugal
| | - Tiago Pereira
- IBMC- Institute for Molecular and Cell Biology, I3S- Institute for Innovation and Health Research, Universidade do Porto, Portugal
| | - João Mouta
- IBMC- Institute for Molecular and Cell Biology, I3S- Institute for Innovation and Health Research, Universidade do Porto, Portugal
| | - Renata Freitas
- IBMC- Institute for Molecular and Cell Biology, I3S- Institute for Innovation and Health Research, Universidade do Porto, Portugal.; ICBAS- Institute of Biomedical Sciences Abel Salazar, Universidade do Porto, Portugal..
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Kim J, Bae DH, Kim JH, Song KS, Kim YS, Kim SY. HOXC10 overexpression promotes cell proliferation and migration in gastric cancer. Oncol Rep 2019; 42:202-212. [PMID: 31115563 PMCID: PMC6549078 DOI: 10.3892/or.2019.7164] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 05/14/2019] [Indexed: 12/24/2022] Open
Abstract
Homeodomain‑containing gene 10 (HOXC10) is a member of the homeobox transcription factors that plays an important role in the development of multicellular organisms. HOXC10 is overexpressed in a variety of human cancers, and recent studies have revealed that HOXC10 is upregulated in gastric cancer as well. However, its mechanism of action is not fully understood, thus, the role of HOXC10 was investigated in the present study in human gastric cancer. First, HOXC10 expression was revealed to be significantly increased in gastric cancer tissues compared to normal tissues (TCGA dataset), and HOXC10 upregulation was associated with decreased recurrence‑free survival in gastric cancer patients in a public gene expression dataset. HOXC10 promoted cell proliferation and metastasis in two gastric cancer cell lines (AGS and MKN74). Analyzing TCGA 450K DNA methylation dataset, it was revealed that HOXC10 CpG sites were hypomethylated in gastric cancer tissues. Bisulfite sequencing revealed that CpG sites in the HOXC10 first intronic region were hypomethylated in three gastric cancer tissues, and HOXC10 expression was increased in gastric cancer cell lines (AGS and SNU620) in response to 5‑azacytidine treatment. By RNA‑sequencing of AGS cells with ectopic HOXC10 expression, it was revealed that many genes were upregulated by HOXC10 overexpression. Among them, CST1 was predicted to be a HOXC10 direct target gene via prediction of HOXC10 binding sites from the JASPAR database. A chromatin immunoprecipitation assay revealed that HOXC10 directly bound to CST1 promoter regions. The present study proposes HOXC10 is a potential prognostic marker or therapeutic target in human gastric cancer.
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Affiliation(s)
- Jina Kim
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Republic of Korea
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Dong-Hyuck Bae
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Republic of Korea
- Genome Editing Research Center, KRIBB, Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Jong Hwan Kim
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Kyu-Sang Song
- Department of Pathology, College of Medicine, Chungnam National University, Yuseong-gu, Daejeon 35015, Republic of Korea
| | - Yong Sung Kim
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Republic of Korea
- Genome Editing Research Center, KRIBB, Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Seon-Young Kim
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Republic of Korea
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea
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8
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Johng D, Torga G, Ewing CM, Jin K, Norris JD, McDonnell DP, Isaacs WB. HOXB13 interaction with MEIS1 modifies proliferation and gene expression in prostate cancer. Prostate 2019; 79:414-424. [PMID: 30560549 DOI: 10.1002/pros.23747] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 11/02/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND The recurrent p.Gly84Glu germline mutation (G84E) in HOXB13 is consistently associated with prostate cancer (PCa), although the mechanisms underlying such linkage remain elusive. The majority of the PCa-associated HOXB13 mutations identified are localized to two conserved domains in HOXB13 that have been shown to mediate the interaction with MEIS cofactors belonging to the TALE family of homeodomain transcription factors. In this study, we sought to interrogate the biochemical and functional interactions between HOXB13 and MEIS in prostatic cells with a goal of defining how the HOXB13-MEIS complex impacts PCa pathobiology and define the extent to which the oncogenic activity of G84E is related to its effect on HOXB13-MEIS interaction/function. METHODS HOXB13 and MEIS paralog expression in prostate epithelial cells and PCa cell lines was characterized by qPCR and immunoblot analyses. HOXB13 and MEIS1 co-expression in human prostate tissue was confirmed by IHC, followed by co-IP mapping of HOXB13-MEIS1 interactions. Proliferation of the PCa cell line LAPC4 following shRNA-mediated knockdown of each gene or both genes was assessed using DNA- and metabolic-based assays. Transcriptional targets of HOXB13 and MEIS1 were identified by gene expression profiling and qPCR. Finally, protein stability of HOXB13 in the context of MEIS1 was determined using pulse-chase assays. RESULTS HOXB13 and MEIS1 are co-expressed and interact in prostate cells. Both of the putative MEIS interacting domains (MID) within HOXB13 were shown to be capable of mediating the interaction between HOXB13 and MEIS1 independently and such interactions were not influenced by the G84E mutation. The inhibitory effect of either HOXB13 or MEIS1 knockdown on cellular proliferation was augmented by knockdown of both genes, and MEIS1 knockdown abolished HOXB13-driven regulation of BCHE and TNFSF10 mRNA expression. Notably, we demonstrated that MEIS1 stabilized the HOXB13 protein in LAPC4 cells. CONCLUSIONS Our study provides evidence for functional HOXB13-MEIS1 interactions in PCa. MEIS1 may contribute to the cancer-promoting actions of HOXB13 in cellular proliferation and gene regulation by prolonging HOXB13 half-life. Our data demonstrates that G84E is not a loss-of-function mutation that interferes with HOXB13 stability or ability to interact with MEIS1.
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Affiliation(s)
- Dorhyun Johng
- Brady Urological Institute, Johns Hopkins University, School of Medicine, Baltimore, Maryland
| | - Gonzalo Torga
- Brady Urological Institute, Johns Hopkins University, School of Medicine, Baltimore, Maryland
| | - Charles M Ewing
- Brady Urological Institute, Johns Hopkins University, School of Medicine, Baltimore, Maryland
| | - Kideok Jin
- Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York
| | - John D Norris
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina
| | - Donald P McDonnell
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina
| | - William B Isaacs
- Brady Urological Institute, Johns Hopkins University, School of Medicine, Baltimore, Maryland
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Draime A, Bridoux L, Belpaire M, Pringels T, Degand H, Morsomme P, Rezsohazy R. The O-GlcNAc transferase OGT interacts with and post-translationally modifies the transcription factor HOXA1. FEBS Lett 2018; 592:1185-1201. [PMID: 29465778 DOI: 10.1002/1873-3468.13015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 01/26/2018] [Accepted: 02/13/2018] [Indexed: 11/06/2022]
Abstract
HOXA1 belongs to the HOX family of transcription factors which are key regulators of animal development. Little is known about the molecular pathways controlling HOXA1. Recent data from our group revealed distinct partner proteins interacting with HOXA1. Among them, OGT is an O-linked N-acetylglucosamine (O-GlcNAc) transferase modifying a variety of proteins involved in different cellular processes including transcription. Here, we confirm OGT as a HOXA1 interactor, we characterise which domains of HOXA1 and OGT are required for the interaction, and we provide evidence that OGT post-translationally modifies HOXA1. Mass spectrometry experiments indeed reveal that HOXA1 can be phosphorylated on the AGGTVGSPQYIHHSY peptide and that upon OGT expression, the phosphate adduct is replaced by an O-GlcNAc group.
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Affiliation(s)
- Amandine Draime
- Animal Molecular and Cellular Biology, Institut des Sciences de la Vie (ISV), Université catholique de Louvain, Louvain-la-Neuve, Belgium
| | - Laure Bridoux
- Animal Molecular and Cellular Biology, Institut des Sciences de la Vie (ISV), Université catholique de Louvain, Louvain-la-Neuve, Belgium
| | - Magali Belpaire
- Animal Molecular and Cellular Biology, Institut des Sciences de la Vie (ISV), Université catholique de Louvain, Louvain-la-Neuve, Belgium
| | - Tamara Pringels
- Animal Molecular and Cellular Biology, Institut des Sciences de la Vie (ISV), Université catholique de Louvain, Louvain-la-Neuve, Belgium
| | - Hervé Degand
- Molecular Physiology, Institut des Sciences de la Vie (ISV), Université catholique de Louvain, Louvain-la-Neuve, Belgium
| | - Pierre Morsomme
- Molecular Physiology, Institut des Sciences de la Vie (ISV), Université catholique de Louvain, Louvain-la-Neuve, Belgium
| | - René Rezsohazy
- Animal Molecular and Cellular Biology, Institut des Sciences de la Vie (ISV), Université catholique de Louvain, Louvain-la-Neuve, Belgium
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10
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Sauvegarde C, Paul D, Bridoux L, Jouneau A, Degrelle S, Hue I, Rezsohazy R, Donnay I. Dynamic Pattern of HOXB9 Protein Localization during Oocyte Maturation and Early Embryonic Development in Mammals. PLoS One 2016; 11:e0165898. [PMID: 27798681 PMCID: PMC5087947 DOI: 10.1371/journal.pone.0165898] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 10/01/2016] [Indexed: 02/06/2023] Open
Abstract
Background We previously showed that the homeodomain transcription factor HOXB9 is expressed in mammalian oocytes and early embryos. However, a systematic and exhaustive study of the localization of the HOXB9 protein, and HOX proteins in general, during mammalian early embryonic development has so far never been performed. Results The distribution of HOXB9 proteins in oocytes and the early embryo was characterized by immunofluorescence from the immature oocyte stage to the peri-gastrulation period in both the mouse and the bovine. HOXB9 was detected at all studied stages with a dynamic expression pattern. Its distribution was well conserved between the two species until the blastocyst stage and was mainly nuclear. From that stage on, trophoblastic cells always showed a strong nuclear staining, while the inner cell mass and the derived cell lines showed important dynamic variations both in staining intensity and in intra-cellular localization. Indeed, HOXB9 appeared to be progressively downregulated in epiblast cells and only reappeared after gastrulation had well progressed. The protein was also detected in the primitive endoderm and its derivatives with a distinctive presence in apical vacuoles of mouse visceral endoderm cells. Conclusions Together, these results could suggest the existence of unsuspected functions for HOXB9 during early embryonic development in mammals.
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Affiliation(s)
- Caroline Sauvegarde
- Biologie Moléculaire et Cellulaire Animale (AMCB), Institut des Sciences de la Vie (ISV), Université catholique de Louvain, Louvain-la-Neuve, Belgium
| | - Delphine Paul
- Biologie Moléculaire et Cellulaire Animale (AMCB), Institut des Sciences de la Vie (ISV), Université catholique de Louvain, Louvain-la-Neuve, Belgium
| | - Laure Bridoux
- Biologie Moléculaire et Cellulaire Animale (AMCB), Institut des Sciences de la Vie (ISV), Université catholique de Louvain, Louvain-la-Neuve, Belgium
| | - Alice Jouneau
- UMR BDR, INRA, ENVA, Université Paris Saclay, Jouy-en-Josas, France
| | - Séverine Degrelle
- Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S1139, U767, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Paris, France
- PremUp Foundation, Paris, France
| | - Isabelle Hue
- UMR BDR, INRA, ENVA, Université Paris Saclay, Jouy-en-Josas, France
| | - René Rezsohazy
- Biologie Moléculaire et Cellulaire Animale (AMCB), Institut des Sciences de la Vie (ISV), Université catholique de Louvain, Louvain-la-Neuve, Belgium
| | - Isabelle Donnay
- Biologie Moléculaire et Cellulaire Animale (AMCB), Institut des Sciences de la Vie (ISV), Université catholique de Louvain, Louvain-la-Neuve, Belgium
- * E-mail:
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11
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Sadik H, Korangath P, Nguyen NK, Gyorffy B, Kumar R, Hedayati M, Teo WW, Park S, Panday H, Munoz TG, Menyhart O, Shah N, Pandita RK, Chang JC, DeWeese T, Chang HY, Pandita TK, Sukumar S. HOXC10 Expression Supports the Development of Chemotherapy Resistance by Fine Tuning DNA Repair in Breast Cancer Cells. Cancer Res 2016; 76:4443-56. [PMID: 27302171 DOI: 10.1158/0008-5472.can-16-0774] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 05/25/2016] [Indexed: 11/16/2022]
Abstract
Development of drug resistance is a major factor limiting the continued success of cancer chemotherapy. To overcome drug resistance, understanding the underlying mechanism(s) is essential. We found that HOXC10 is overexpressed in primary carcinomas of the breast, and even more significantly in distant metastasis arising after failed chemotherapy. High HOXC10 expression correlates with shorter recurrence-free and overall survival in patients with estrogen receptor-negative breast cancer undergoing chemotherapy. We found that HOXC10 promotes survival in cells treated with doxorubicin, paclitaxel, or carboplatin by suppressing apoptosis and upregulating NF-κB Overexpressed HOXC10 increases S-phase-specific DNA damage repair by homologous recombination (HR) and checkpoint recovery in cells at three important phases. For double-strand break repair, HOXC10 recruits HR proteins at sites of DNA damage. It enhances resection and lastly, it resolves stalled replication forks, leading to initiation of DNA replication following DNA damage. We show that HOXC10 facilitates, but is not directly involved in DNA damage repair mediated by HR. HOXC10 achieves integration of these functions by binding to, and activating cyclin-dependent kinase, CDK7, which regulates transcription by phosphorylating the carboxy-terminal domain of RNA polymerase II. Consistent with these findings, inhibitors of CDK7 reverse HOXC10-mediated drug resistance in cultured cells. Blocking HOXC10 function, therefore, presents a promising new strategy to overcome chemotherapy resistance in breast cancer. Cancer Res; 76(15); 4443-56. ©2016 AACR.
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Affiliation(s)
- Helen Sadik
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Preethi Korangath
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Nguyen K Nguyen
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Balazs Gyorffy
- MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary. 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Rakesh Kumar
- Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Mohammad Hedayati
- Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Wei Wen Teo
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Sunju Park
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Hardik Panday
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Teresa Gonzalez Munoz
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Otilia Menyhart
- MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary. 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Nilay Shah
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Raj K Pandita
- Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, Texas
| | - Jenny C Chang
- Methodist Cancer Center, The Houston Methodist Research Institute, Houston, Texas
| | - Theodore DeWeese
- Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Howard Y Chang
- Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California
| | - Tej K Pandita
- Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, Texas.
| | - Saraswati Sukumar
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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12
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Abstract
Metazoans encode clusters of paralogous Hox genes that are critical for proper development of the body plan. However, there are a number of unresolved issues regarding how paralogous Hox factors achieve specificity to control distinct cell fates. First, how do Hox paralogs, which have very similar DNA binding preferences in vitro, drive different transcriptional programs in vivo? Second, the number of potential Hox binding sites within the genome is vast compared to the number of sites bound. Hence, what determines where in the genome Hox factors bind? Third, what determines whether a Hox factor will activate or repress a specific target gene? Here, we review the current evidence that is beginning to shed light onto these questions. In particular, we highlight how cooperative interactions with other transcription factors (especially PBC and HMP proteins) and the sequences of cis-regulatory modules provide a basis for the mechanisms of Hox specificity. We conclude by integrating a number of the concepts described throughout the review in a case study of a highly interrogated Drosophila cis-regulatory module named “The Distal-less Conserved Regulatory Element” (DCRE).
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Affiliation(s)
- Arya Zandvakili
- Molecular and Developmental Biology Graduate Program, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
- Medical-Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA;
| | - Brian Gebelein
- Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
- Correspondence: ; Tel.: +1-513-636-3366
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13
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Rezsohazy R, Saurin AJ, Maurel-Zaffran C, Graba Y. Cellular and molecular insights into Hox protein action. Development 2016; 142:1212-27. [PMID: 25804734 DOI: 10.1242/dev.109785] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hox genes encode homeodomain transcription factors that control morphogenesis and have established functions in development and evolution. Hox proteins have remained enigmatic with regard to the molecular mechanisms that endow them with specific and diverse functions, and to the cellular functions that they control. Here, we review recent examples of Hox-controlled cellular functions that highlight their versatile and highly context-dependent activity. This provides the setting to discuss how Hox proteins control morphogenesis and organogenesis. We then summarise the molecular modalities underlying Hox protein function, in particular in light of current models of transcription factor function. Finally, we discuss how functional divergence between Hox proteins might be achieved to give rise to the many facets of their action.
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Affiliation(s)
- René Rezsohazy
- Institut des Sciences de la Vie, Université Catholique de Louvain, Louvain-la-Neuve B-1348, Belgium
| | - Andrew J Saurin
- Aix Marseille Université, CNRS, IBDM, UMR 7288, Marseille 13288, Cedex 09, France
| | | | - Yacine Graba
- Aix Marseille Université, CNRS, IBDM, UMR 7288, Marseille 13288, Cedex 09, France
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14
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Bridoux L, Deneyer N, Bergiers I, Rezsohazy R. Molecular Analysis of the HOXA2-Dependent Degradation of RCHY1. PLoS One 2015; 10:e0141347. [PMID: 26496426 PMCID: PMC4619689 DOI: 10.1371/journal.pone.0141347] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 10/07/2015] [Indexed: 01/19/2023] Open
Abstract
The homeodomain transcription factor Hoxa2 interacts with the RING-finger type E3 ubiquitin ligase RCHY1 and induces its proteasomal degradation. In this work, we dissected this non-transcriptional activity of Hoxa2 at the molecular level. The Hoxa2-mediated decay of RCHY1 involves both the 19S and 20S proteasome complexes. It relies on both the Hoxa2 homeodomain and C-terminal moiety although no single deletion in the Hoxa2 sequence could disrupt the RCHY1 interaction. That the Hoxa2 homeodomain alone could mediate RCHY1 binding is consistent with the shared ability all the Hox proteins we tested to interact with RCHY1. Nonetheless, the ability to induce RCHY1 degradation although critically relying on the homeodomain is not common to all Hox proteins. This identifies the homeodomain as necessary but not sufficient for what appears to be an almost generic Hox protein activity. Finally we provide evidence that the Hoxa2-induced degradation of RCHY1 is evolutionarily conserved among vertebrates. These data therefore support the hypothesis that the molecular and functional interaction between Hox proteins and RCHY1 is an ancestral Hox property.
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Affiliation(s)
- Laure Bridoux
- From the Animal Molecular and Cellular Biology group (AMCB), Life Sciences Institute (ISV), Université catholique de Louvain, Louvain-la-Neuve, Belgium
| | - Noémie Deneyer
- From the Animal Molecular and Cellular Biology group (AMCB), Life Sciences Institute (ISV), Université catholique de Louvain, Louvain-la-Neuve, Belgium
| | - Isabelle Bergiers
- From the Animal Molecular and Cellular Biology group (AMCB), Life Sciences Institute (ISV), Université catholique de Louvain, Louvain-la-Neuve, Belgium
| | - René Rezsohazy
- From the Animal Molecular and Cellular Biology group (AMCB), Life Sciences Institute (ISV), Université catholique de Louvain, Louvain-la-Neuve, Belgium
- * E-mail:
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15
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Gou Y, Zhang T, Xu J. Transcription Factors in Craniofacial Development: From Receptor Signaling to Transcriptional and Epigenetic Regulation. Curr Top Dev Biol 2015; 115:377-410. [PMID: 26589933 DOI: 10.1016/bs.ctdb.2015.07.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Craniofacial morphogenesis is driven by spatial-temporal terrains of gene expression, which give rise to stereotypical pattern formation. Transcription factors are key cellular components that control these gene expressions. They are information hubs that integrate inputs from extracellular factors and environmental cues, direct epigenetic modifications, and define transcriptional status. These activities allow transcription factors to confer specificity and potency to transcription regulation during development.
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Affiliation(s)
- Yongchao Gou
- State Key Laboratory of Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, Los Angeles, USA
| | - Tingwei Zhang
- Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, Los Angeles, USA; State Key Laboratory of Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jian Xu
- Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, Los Angeles, USA.
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16
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Meng M, Cheng DJ, Peng J, Qian WL, Li JR, Dai DD, Zhang TL, Xia QY. The homeodomain transcription factors antennapedia and POU-M2 regulate the transcription of the steroidogenic enzyme gene Phantom in the silkworm. J Biol Chem 2015; 290:24438-52. [PMID: 26253172 DOI: 10.1074/jbc.m115.651810] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Indexed: 12/22/2022] Open
Abstract
The steroid hormone ecdysone, which controls insect molting and metamorphosis, is synthesized in the prothoracic gland (PG), and several steroidogenic enzymes that are expressed specifically in the PG are involved in ecdysteroidogenesis. In this study, we identified new regulators that are involved in the transcriptional control of the silkworm steroidogenic enzyme genes. In silico analysis predicted several potential cis-regulatory elements (CREs) for the homeodomain transcription factors Antennapedia (Antp) and POU-M2 in the proximal promoters of steroidogenic enzyme genes. Antp and POU-M2 are expressed dynamically in the PG during larval development, and their overexpression in silkworm embryo-derived (BmE) cells induced the expression of steroidogenic enzyme genes. Importantly, luciferase reporter analyses, electrophoretic mobility shift assays, and chromatin immunoprecipitation assays revealed that Antp and POU-M2 promote the transcription of the silkworm steroidogenic enzyme gene Phantom (Phm) by binding directly to specific motifs within overlapping CREs in the Phm promoter. Mutations of these CREs in the Phm promoter suppressed the transcriptional activities of both Antp and POU-M2 in BmE cells and decreased the activities of mutated Phm promoters in the silkworm PG. In addition, pulldown and co-immunoprecipitation assays demonstrated that Antp can interact with POU-M2. Moreover, RNA interference-mediated down-regulation of either Antp or POU-M2 during silkworm wandering not only decreased the ecdysone titer but also led to the failure of metamorphosis. In summary, our results suggest that Antp and POU-M2 coordinate the transcription of the silkworm Phm gene directly, indicating new roles for homeodomain proteins in regulating insect ecdysteroidogenesis.
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Affiliation(s)
- Meng Meng
- From the State Key Laboratory of Silkworm Genome Biology and the Key Sericultural Laboratory of the Ministry of Agriculture, College of Biotechnology, Southwest University, Chongqing 400715, China
| | - Dao-Jun Cheng
- From the State Key Laboratory of Silkworm Genome Biology and the Key Sericultural Laboratory of the Ministry of Agriculture, College of Biotechnology, Southwest University, Chongqing 400715, China
| | - Jian Peng
- From the State Key Laboratory of Silkworm Genome Biology and the Key Sericultural Laboratory of the Ministry of Agriculture, College of Biotechnology, Southwest University, Chongqing 400715, China
| | - Wen-Liang Qian
- From the State Key Laboratory of Silkworm Genome Biology and the Key Sericultural Laboratory of the Ministry of Agriculture, College of Biotechnology, Southwest University, Chongqing 400715, China
| | - Jia-Rui Li
- From the State Key Laboratory of Silkworm Genome Biology and the Key Sericultural Laboratory of the Ministry of Agriculture, College of Biotechnology, Southwest University, Chongqing 400715, China
| | - Dan-Dan Dai
- From the State Key Laboratory of Silkworm Genome Biology and the Key Sericultural Laboratory of the Ministry of Agriculture, College of Biotechnology, Southwest University, Chongqing 400715, China
| | - Tian-Lei Zhang
- From the State Key Laboratory of Silkworm Genome Biology and the Key Sericultural Laboratory of the Ministry of Agriculture, College of Biotechnology, Southwest University, Chongqing 400715, China
| | - Qing-You Xia
- From the State Key Laboratory of Silkworm Genome Biology and the Key Sericultural Laboratory of the Ministry of Agriculture, College of Biotechnology, Southwest University, Chongqing 400715, China
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17
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Abstract
Signaling classically involves the secretion of diverse molecules that bind specific cell-surface receptors and engage intracellular transduction cascades. Some exceptions-namely, lipophilic agents-can cross plasma membranes to bind intracellular receptors and be carried to the nucleus to regulate transcription. Homeoprotein transcription factors are among the few proteins with such a capacity. Here, we review the signaling activities of homeoproteins in the developing and adult nervous system, with particular emphasis on axon/cell migration and postnatal critical periods of cerebral cortex plasticity. We also describe homeoprotein non-cell-autonomous mechanisms and explore how this "novel" signaling pathway impacts emerging research in brain development and physiology. In this context, we explore hypotheses on the evolution of signaling, the role of homeoproteins as early morphogens, and their therapeutic potential for neurological and psychiatric diseases.
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18
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Role of HOXA9 in leukemia: dysregulation, cofactors and essential targets. Oncogene 2015; 35:1090-8. [PMID: 26028034 DOI: 10.1038/onc.2015.174] [Citation(s) in RCA: 132] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 03/24/2015] [Accepted: 04/14/2015] [Indexed: 02/08/2023]
Abstract
HOXA9 is a homeodomain-containing transcription factor that has an important role in hematopoietic stem cell expansion and is commonly deregulated in acute leukemias. A variety of upstream genetic alterations in acute myeloid leukemia lead to overexpression of HOXA9, which is a strong predictor of poor prognosis. In many cases, HOXA9 has been shown to be necessary for maintaining leukemic transformation; however, the molecular mechanisms through which it promotes leukemogenesis remain elusive. Recent work has established that HOXA9 regulates downstream gene expression through binding at promoter distal enhancers along with a subset of cell-specific cofactor and collaborator proteins. Increasing efforts are being made to identify both the critical cofactors and target genes required for maintaining transformation in HOXA9-overexpressing leukemias. With continued advances in understanding HOXA9-mediated transformation, there is a wealth of opportunity for developing novel therapeutics that would be applicable for greater than 50% of AML with overexpression of HOXA9.
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19
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Prochiantz A, Fuchs J, Di Nardo AA. Postnatal signalling with homeoprotein transcription factors. Philos Trans R Soc Lond B Biol Sci 2015; 369:rstb.2013.0518. [PMID: 25135979 DOI: 10.1098/rstb.2013.0518] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Homeoprotein (HP) transcription factors were originally identified for their embryonic cell-autonomous developmental functions. In this review, we discuss their postnatal and adult physiological functions based on the study of Otx2, Engrailed-1 and Engrailed-2 (collectively Engrailed). For Engrailed, we discuss its function in the cell-autonomous regulation of ventral midbrain dopaminergic neuron survival and physiology and in the non-cell-autonomous maintenance of axons. For Otx2, we describe how the protein is expressed in the choroid plexus and transported into cortical parvalbumin cells where it regulates plasticity in the visual cortex. These two examples illustrate how the understanding of HP postnatal and adult functions, including signalling functions, may lead to the identification of disease-associated genetic pathways and to the development of original therapeutic strategies.
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Affiliation(s)
- Alain Prochiantz
- CIRB, CNRS UMR 7241/INSERM U1050, College de France, 11 place Marcelin Berthelot, Paris Cedex 05 75231, France
| | - Julia Fuchs
- CIRB, CNRS UMR 7241/INSERM U1050, College de France, 11 place Marcelin Berthelot, Paris Cedex 05 75231, France
| | - Ariel A Di Nardo
- CIRB, CNRS UMR 7241/INSERM U1050, College de France, 11 place Marcelin Berthelot, Paris Cedex 05 75231, France
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20
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Zhou B, Liu C, Zhu G. (1)H, (15)N and (13)C chemical shift assignments of the homeodomain of Hoxc9 in complex with the cell cycle regulator Geminin. BIOMOLECULAR NMR ASSIGNMENTS 2015; 9:165-168. [PMID: 25092235 DOI: 10.1007/s12104-014-9566-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Accepted: 07/04/2014] [Indexed: 06/03/2023]
Abstract
Homeodomain-containing transcription factors including Hox proteins play fundamental roles in the regulation of different cellular and developmental processes. These proteins all contain a homeodomain, which is a 60-amino acid DNA binding domain encoded by a 180-base pair DNA sequence. Homeodomains also serve as protein interaction targets to regulate the functions of these transcription factors or other proteins. The cell cycle regulator Geminin interacts with Hox homeodomains to inhibit the transcription activities of Hox proteins and enrolls Hox proteins in the cell proliferation process. Here we report complete chemical shift assignments of the homeodomain of Hoxc9 (Hoxc9-HD) in complex with the homeodomain binding region of Geminin (Gem-HBR), which were determined by triple resonance NMR experiments. These resonance assignments provide a basis for the structure determination of the Hoxc9-HD/Gem-HBR complex and for the further study of homeodomains in complex with other regulatory protein partners (BMRB deposits with accession number 17407).
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Affiliation(s)
- Bo Zhou
- Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong
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21
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Freund JN, Duluc I, Reimund JM, Gross I, Domon-Dell C. Extending the functions of the homeotic transcription factor Cdx2 in the digestive system through nontranscriptional activities. World J Gastroenterol 2015; 21:1436-1443. [PMID: 25663763 PMCID: PMC4316086 DOI: 10.3748/wjg.v21.i5.1436] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Revised: 11/25/2014] [Accepted: 12/16/2014] [Indexed: 02/06/2023] Open
Abstract
The homeoprotein encoded by the intestinal-specific Cdx2 gene is a major regulator of gut development and homeostasis, also involved in colon cancer as well as in intestinal-type metaplasias when it is abnormally expressed outside the gut. At the molecular level, structure/function studies have demonstrated that the Cdx2 protein is a transcription factor containing a conserved homeotic DNA-binding domain made of three alpha helixes arranged in a helix-turn-helix motif, preceded by a transcriptional domain and followed by a regulatory domain. The protein interacts with several thousand sites on the chromatin and widely regulates intestinal functions in stem/progenitor cells as well as in mature differentiated cells. Yet, this transcription factor also acts trough original nontranscriptional mechanisms. Indeed, the identification of novel protein partners of Cdx2 and also of a splicing variant revealed unexpected functions in the control of signaling pathways like the Wnt and NF-κB pathways, in double-strand break DNA repair and in premessenger RNA splicing. These novel functions of Cdx2 must be considered to fully understand the complexity of the role of Cdx2 in the healthy intestine and in diseases.
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22
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Bergiers I, Lambert B, Daakour S, Twizere JC, Rezsohazy R. Hox protein interactions: screening and network building. Methods Mol Biol 2014; 1196:319-48. [PMID: 25151173 DOI: 10.1007/978-1-4939-1242-1_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Understanding the mode of action of Hox proteins requires the identification of molecular and cellular pathways they take part in. This includes to characterize the networks of protein-protein interactions involving Hox proteins. In this chapter we propose a strategy and methods to map Hox interaction networks, from yeast two-hybrid and high-throughput yeast two-hybrid interaction screening to bioinformatic analyses based on the software platform Cytoscape.
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Affiliation(s)
- Isabelle Bergiers
- Institut des Sciences de la Vie, Université catholique de Louvain, Croix du Sud 4-5 box L7.07.10, Louvain-la-Neuve, 1348, Belgium
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