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1.
PLoS Genet ; 11(3): e1005034, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25757017

RESUMO

Lysine acetylation has recently emerged as an important post-translational modification in diverse organisms, but relatively little is known about its roles in mammalian development and stem cells. Bromodomain- and PHD finger-containing protein 1 (BRPF1) is a multidomain histone binder and a master activator of three lysine acetyltransferases, MOZ, MORF and HBO1, which are also known as KAT6A, KAT6B and KAT7, respectively. While the MOZ and MORF genes are rearranged in leukemia, the MORF gene is also mutated in prostate and other cancers and in four genetic disorders with intellectual disability. Here we show that forebrain-specific inactivation of the mouse Brpf1 gene causes hypoplasia in the dentate gyrus, including underdevelopment of the suprapyramidal blade and complete loss of the infrapyramidal blade. We trace the developmental origin to compromised Sox2+ neural stem cells and Tbr2+ intermediate neuronal progenitors. We further demonstrate that Brpf1 loss deregulates neuronal migration, cell cycle progression and transcriptional control, thereby causing abnormal morphogenesis of the hippocampus. These results link histone binding and acetylation control to hippocampus development and identify an important epigenetic regulator for patterning the dentate gyrus, a brain structure critical for learning, memory and adult neurogenesis.


Assuntos
Proteínas de Transporte/genética , Giro Denteado/metabolismo , Epigênese Genética/genética , Histona Acetiltransferases/metabolismo , Morfogênese/genética , Acetilação , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proteínas de Transporte/metabolismo , Diferenciação Celular/genética , Proteínas de Ligação a DNA , Giro Denteado/crescimento & desenvolvimento , Giro Denteado/patologia , Hipocampo/crescimento & desenvolvimento , Hipocampo/patologia , Histona Acetiltransferases/genética , Histonas/metabolismo , Humanos , Camundongos , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Prosencéfalo/embriologia , Prosencéfalo/crescimento & desenvolvimento , Prosencéfalo/metabolismo , Processamento de Proteína Pós-Traducional/genética , Proteínas com Domínio T/genética
2.
J Biol Chem ; 290(11): 7114-29, 2015 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-25568313

RESUMO

Epigenetic mechanisms are important in different neurological disorders, and one such mechanism is histone acetylation. The multivalent chromatin regulator BRPF1 (bromodomain- and plant homeodomain-linked (PHD) zinc finger-containing protein 1) recognizes different epigenetic marks and activates three histone acetyltransferases, so it is both a reader and a co-writer of the epigenetic language. The three histone acetyltransferases are MOZ, MORF, and HBO1, which are also known as lysine acetyltransferase 6A (KAT6A), KAT6B, and KAT7, respectively. The MORF gene is mutated in four neurodevelopmental disorders sharing the characteristic of intellectual disability and frequently displaying callosal agenesis. Here, we report that forebrain-specific inactivation of the mouse Brpf1 gene caused early postnatal lethality, neocortical abnormalities, and partial callosal agenesis. With respect to the control, the mutant forebrain contained fewer Tbr2-positive intermediate neuronal progenitors and displayed aberrant neurogenesis. Molecularly, Brpf1 loss led to decreased transcription of multiple genes, such as Robo3 and Otx1, important for neocortical development. Surprisingly, elevated expression of different Hox genes and various other transcription factors, such as Lhx4, Foxa1, Tbx5, and Twist1, was also observed. These results thus identify an important role of Brpf1 in regulating forebrain development and suggest that it acts as both an activator and a silencer of gene expression in vivo.


Assuntos
Agenesia do Corpo Caloso/genética , Encéfalo/anormalidades , Encéfalo/crescimento & desenvolvimento , Proteínas de Transporte/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Adaptadoras de Transdução de Sinal , Agenesia do Corpo Caloso/metabolismo , Animais , Comportamento Animal , Encéfalo/metabolismo , Proteínas de Transporte/metabolismo , Corpo Caloso/crescimento & desenvolvimento , Corpo Caloso/metabolismo , Proteínas de Ligação a DNA , Deleção de Genes , Inativação Gênica , Camundongos , Camundongos Knockout , Neurogênese , Ativação Transcricional
3.
J Biol Chem ; 290(18): 11349-64, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25773539

RESUMO

With hundreds of chromatin regulators identified in mammals, an emerging issue is how they modulate biological and pathological processes. BRPF1 (bromodomain- and PHD finger-containing protein 1) is a unique chromatin regulator possessing two PHD fingers, one bromodomain and a PWWP domain for recognizing multiple histone modifications. In addition, it binds to the acetyltransferases MOZ, MORF, and HBO1 (also known as KAT6A, KAT6B, and KAT7, respectively) to promote complex formation, restrict substrate specificity, and enhance enzymatic activity. We have recently showed that ablation of the mouse Brpf1 gene causes embryonic lethality at E9.5. Here we present systematic analyses of the mutant animals and demonstrate that the ablation leads to vascular defects in the placenta, yolk sac, and embryo proper, as well as abnormal neural tube closure. At the cellular level, Brpf1 loss inhibits proliferation of embryonic fibroblasts and hematopoietic progenitors. Molecularly, the loss reduces transcription of a ribosomal protein L10 (Rpl10)-like gene and the cell cycle inhibitor p27, and increases expression of the cell-cycle inhibitor p16 and a novel protein homologous to Scp3, a synaptonemal complex protein critical for chromosome association and embryo survival. These results uncover a crucial role of Brpf1 in controlling mouse embryo development and regulating cellular and gene expression programs.


Assuntos
Proteínas de Transporte/metabolismo , Cromatina/metabolismo , Desenvolvimento Embrionário , Proteínas Adaptadoras de Transdução de Sinal , Animais , Linhagem Celular , Proliferação de Células , Proteínas de Ligação a DNA , Feminino , Fibroblastos/citologia , Hematopoese , Camundongos , Neovascularização Fisiológica , Defeitos do Tubo Neural/metabolismo , Placenta/irrigação sanguínea , Placenta/metabolismo , Gravidez , Saco Vitelino/irrigação sanguínea , Saco Vitelino/embriologia
5.
Sci Immunol ; 7(70): eabi5072, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35363543

RESUMO

Melanoma is an immunogenic cancer with a high response rate to immune checkpoint inhibitors (ICIs). It harbors a high mutation burden compared with other cancers and, as a result, has abundant tumor-infiltrating lymphocytes (TILs) within its microenvironment. However, understanding the complex interplay between the stroma, tumor cells, and distinct TIL subsets remains a substantial challenge in immune oncology. To properly study this interplay, quantifying spatial relationships of multiple cell types within the tumor microenvironment is crucial. To address this, we used cytometry time-of-flight (CyTOF) imaging mass cytometry (IMC) to simultaneously quantify the expression of 35 protein markers, characterizing the microenvironment of 5 benign nevi and 67 melanomas. We profiled more than 220,000 individual cells to identify melanoma, lymphocyte subsets, macrophage/monocyte, and stromal cell populations, allowing for in-depth spatial quantification of the melanoma microenvironment. We found that within pretreatment melanomas, the abundance of proliferating antigen-experienced cytotoxic T cells (CD8+CD45RO+Ki67+) and the proximity of antigen-experienced cytotoxic T cells to melanoma cells were associated with positive response to ICIs. Our study highlights the potential of multiplexed single-cell technology to quantify spatial cell-cell interactions within the tumor microenvironment to understand immune therapy responses.


Assuntos
Melanoma , Humanos , Citometria por Imagem , Linfócitos do Interstício Tumoral , Linfócitos T Citotóxicos , Microambiente Tumoral
6.
Commun Biol ; 3(1): 310, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546838

RESUMO

Subsets of breast tumors present major clinical challenges, including triple-negative, metastatic/recurrent disease and rare histologies. Here, we developed 37 patient-derived xenografts (PDX) from these difficult-to-treat cancers to interrogate their molecular composition and functional biology. Whole-genome and transcriptome sequencing and reverse-phase protein arrays revealed that PDXs conserve the molecular landscape of their corresponding patient tumors. Metastatic potential varied between PDXs, where low-penetrance lung micrometastases were most common, though a subset of models displayed high rates of dissemination in organotropic or diffuse patterns consistent with what was observed clinically. Chemosensitivity profiling was performed in vivo with standard-of-care agents, where multi-drug chemoresistance was retained upon xenotransplantation. Consolidating chemogenomic data identified actionable features in the majority of PDXs, and marked regressions were observed in a subset that was evaluated in vivo. Together, this clinically-annotated PDX library with comprehensive molecular and phenotypic profiling serves as a resource for preclinical studies on difficult-to-treat breast tumors.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Endogâmicos NOD , Mutação , Medicina de Precisão , Prognóstico , Estudo de Prova de Conceito , Análise Serial de Proteínas/métodos , Sequenciamento Completo do Genoma
7.
J Cell Biochem ; 104(5): 1541-52, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18425769

RESUMO

Histone deacetylase (HDAC) activity was first discovered about 40 years ago, but it was not until the molecular identification of the first HDACs in 1996 that this family of enzymes gained prominence. In addition to histones, HDACs reverse lysine acetylation of various non-histone proteins located in the nucleus and the cytoplasm. Here, we examine the nuclear roles of these enzymes, with a specific focus on their active crosstalk with different chromatin regulators.


Assuntos
Núcleo Celular/enzimologia , Histona Desacetilases/metabolismo , Transdução de Sinais , Sequência de Aminoácidos , Animais , Genoma/genética , Histona Desacetilases/química , Humanos , Dados de Sequência Molecular , Subunidades Proteicas/metabolismo , Sirtuínas/metabolismo
8.
Stem Cell Reports ; 8(4): 1018-1031, 2017 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-28285879

RESUMO

During prostate development, basal and luminal cell lineages are generated through symmetric and asymmetric divisions of bipotent basal cells. However, the extent to which spindle orientation controls division symmetry or cell fate, and the upstream factors regulating this process, are still elusive. We report that GATA3 is expressed in both prostate basal progenitor and luminal cells and that loss of GATA3 leads to a mislocalization of PRKCZ, resulting in mitotic spindle randomization during progenitor cell division. Inherently proliferative intermediate progenitor cells accumulate, leading to an expansion of the luminal compartment. These defects ultimately result in a loss of tissue polarity and defective branching morphogenesis. We further show that disrupting the interaction between PRKCZ and PARD6B is sufficient to recapitulate the spindle and cell lineage phenotypes. Collectively, these results identify a critical role for GATA3 in prostate lineage specification, and further highlight the importance of regulating spindle orientation for hierarchical cell lineage organization.


Assuntos
Células Epiteliais/citologia , Fator de Transcrição GATA3/metabolismo , Próstata/crescimento & desenvolvimento , Fuso Acromático/metabolismo , Células-Tronco/citologia , Animais , Polaridade Celular , Células Epiteliais/metabolismo , Fator de Transcrição GATA3/análise , Fator de Transcrição GATA3/genética , Deleção de Genes , Masculino , Camundongos Endogâmicos C57BL , Próstata/citologia , Próstata/ultraestrutura , Proteína Quinase C/análise , Proteína Quinase C/metabolismo , Fuso Acromático/genética , Fuso Acromático/ultraestrutura , Células-Tronco/metabolismo
9.
Cell Rep ; 21(5): 1140-1149, 2017 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-29091754

RESUMO

Therapies targeting epidermal growth factor receptor (EGFR) have variable and unpredictable responses in breast cancer. Screening triple-negative breast cancer (TNBC) patient-derived xenografts (PDXs), we identify a subset responsive to EGFR inhibition by gefitinib, which displays heterogeneous expression of wild-type EGFR. Deep single-cell RNA sequencing of 3,500 cells from an exceptional responder identified subpopulations displaying distinct biological features, where elevated EGFR expression was significantly enriched in a mesenchymal/stem-like cellular cluster. Sorted EGFRhi subpopulations exhibited enhanced stem-like features, including ALDH activity, sphere-forming efficiency, and tumorigenic and metastatic potential. EGFRhi cells gave rise to EGFRhi and EGFRlo cells in primary and metastatic tumors, demonstrating an EGFR-dependent expansion and hierarchical state transition. Similar tumorigenic EGFRhi subpopulations were identified in independent PDXs, where heterogeneous EGFR expression correlated with gefitinib sensitivity. This provides new understanding for an EGFR-dependent hierarchy in TNBC and for patient stratification for therapeutic intervention.


Assuntos
Receptores ErbB/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Animais , Proteína BRCA1/metabolismo , Feminino , Gefitinibe , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Microscopia de Fluorescência , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , RNA Neoplásico/química , RNA Neoplásico/isolamento & purificação , RNA Neoplásico/metabolismo , Análise de Sequência de RNA , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Nucleic Acids Res ; 30(5): 1114-23, 2002 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-11861901

RESUMO

Histone acetylation is important for regulating chromatin structure and gene expression. Three classes of mammalian histone deacetylases have been identified. Among class II, there are five known members, namely HDAC4, HDAC5, HDAC6, HDAC7 and HDAC9. Here we describe the identification and characterization of a novel class II member termed HDAC10. It is a 669 residue polypeptide with a bipartite modular structure consisting of an N-terminal Hda1p-related putative deacetylase domain and a C-terminal leucine-rich domain. HDAC10 is widely expressed in adult human tissues and cultured mammalian cells. It is enriched in the cytoplasm and this enrichment is not sensitive to leptomycin B, a specific inhibitor known to block the nuclear export of other class II members. The leucine-rich domain of HDAC10 is responsible for its cytoplasmic enrichment. Recombinant HDAC10 protein possesses histone deacetylase activity, which is sensitive to trichostatin A, a specific inhibitor for known class I and class II histone deacetylases. When tethered to a promoter, HDAC10 is able to repress transcription. Furthermore, HDAC10 interacts with HDAC3 but not with HDAC4 or HDAC6. These results indicate that HDAC10 is a novel class II histone deacetylase possessing a unique leucine-rich domain.


Assuntos
Histona Desacetilases/genética , Histona Desacetilases/fisiologia , Leucina/química , Sequência de Aminoácidos , Animais , Linhagem Celular , Clonagem Molecular , Citoplasma/metabolismo , Genes Reporter , Células HeLa , Histona Desacetilases/química , Humanos , Camundongos , Dados de Sequência Molecular , Estrutura Terciária de Proteína , RNA Mensageiro/biossíntese , Ratos , Proteínas Repressoras/química , Proteínas Repressoras/genética , Proteínas Repressoras/fisiologia , Homologia de Sequência de Aminoácidos , Distribuição Tecidual , Transcrição Gênica
11.
Methods Mol Biol ; 1458: 13-25, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27581011

RESUMO

Laser capture microdissection (or LCM) allows for isolation of cells from specific tissue compartments, which can then be followed by DNA, RNA, and/or protein isolation and downstream characterization. Unlike other methods for cell isolation, LCM can be directed towards cells situated in specific anatomical contexts, and is therefore of significant value when investigating the tumor microenvironment, where localization is often key to function. Here, we present a summary of ways in which LCM can be utilized, as well as protocols for the isolation of tumor and tumor-associated stromal elements from frozen breast cancer samples, with a focus on preparation of samples for RNA characterization.


Assuntos
Lasers , Microdissecção/métodos , Neoplasias/patologia , Células Estromais/patologia , Biomarcadores , Humanos , Hibridização In Situ/métodos , Neoplasias/genética , Neoplasias/metabolismo , Células Estromais/metabolismo
12.
Oncogene ; 22(51): 8316-29, 2003 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-14614455

RESUMO

The tumor suppressor p53-related p73 shares significant amino-acid sequence identity with p53. Like p53, p73 recognizes canonical p53 DNA-binding sites and activates p53-responsive target genes and induces apoptosis. Moreover, transcription coactivator p300/CBP binds to and coactivates with both p53 and p73 in stimulating the expression of their target genes. Here, we report that coactivator PCAF binds to p73. The N-terminal transactivation domain (TAD) and the conserved oligomerization domain (OD) of p73 are both required for its interaction with PCAF. Conversely, PCAF's HAT-domain is required for and both the N-terminal region and Bromo domain enhance binding of PCAF to p73. Significantly, PCAF stimulates p73-mediated transactivation, and binding of PCAF to p73 is necessary for p73's transactivation activity. PCAF-specific siRNA dramatically reduces p73-mediated transactivation. Stimulation of p73-mediated transactivation by PCAF requires the HAT domain of PCAF and the p53-binding site within the p21 promoter. In vivo, coexpression of wild-type, but not HAT-deficient PCAF with p73beta markedly increases p21 expression. Furthermore, cotransfection of PCAF and p73 leads to increased apoptosis and reduced colony formation. Collectively, these data suggest that p73 recruit PCAF to specific promoters to activate the transcription of p73 target genes.


Assuntos
Proteínas de Ligação a DNA/fisiologia , Proteínas Nucleares/fisiologia , Transativadores/fisiologia , Ativação Transcricional/fisiologia , Apoptose , Sequência de Bases , Linhagem Celular Tumoral , Genes Supressores de Tumor , Humanos , RNA , Proteína Tumoral p73 , Proteínas Supressoras de Tumor , Técnicas do Sistema de Duplo-Híbrido
13.
J Clin Invest ; 121(10): 3789-96, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21965335

RESUMO

Breast cancer, rather than constituting a monolithic entity, comprises heterogeneous tumors with different clinical characteristics, disease courses, and responses to specific treatments. Tumor-intrinsic features, including classical histological and immunopathological classifications as well as more recently described molecular subtypes, separate breast tumors into multiple groups. Tumor-extrinsic features, including microenvironmental configuration, also have prognostic significance and further expand the list of tumor-defining variables. A better understanding of the features underlying heterogeneity, as well as of the mechanisms and consequences of their interactions, is essential to improve targeting of existing therapies and to develop novel agents addressing specific combinations of features.


Assuntos
Neoplasias da Mama/etiologia , Neoplasias da Mama/patologia , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Progressão da Doença , Feminino , Humanos , MicroRNAs/genética , Modelos Biológicos , Metástase Neoplásica/patologia , Células Neoplásicas Circulantes , RNA Neoplásico/genética , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Transcriptoma , Microambiente Tumoral
14.
Clin Cancer Res ; 16(7): 2147-56, 2010 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20215530

RESUMO

PURPOSE: Although the murine orthologue of glycoprotein nonmetastatic B (GPNMB), Osteoactivin, promotes breast cancer metastasis in an in vivo mouse model, its importance in human breast cancer is unknown. We have examined the significance of GPNMB expression as a prognostic indicator of recurrence and assessed its potential as a novel therapeutic target in breast cancer. EXPERIMENTAL DESIGN: The clinical significance of GPNMB expression in breast cancer was addressed by analyzing GPNMB levels in several published gene expression data sets and two independent tissue microarrays derived from human breast tumors. GPNMB-expressing human breast cancer cell lines were further used to validate a toxin-conjugated anti-GPNMB antibody as a novel therapeutic agent. RESULTS: GPNMB expression correlates with shorter recurrence times and reduced overall survival of breast cancer patients. Epithelial-specific GPNMB staining is an independent prognostic indicator for breast cancer recurrence. GPNMB is highly expressed in basal and triple-negative breast cancers and is associated with increased risk of recurrence within this subtype. GPNMB expression confers a more migratory and invasive phenotype on breast cancer cells and sensitizes them to killing by CDX-011 (glembatumumab vedotin), a GPNMB-targeted antibody-drug conjugate. CONCLUSIONS: GPNMB expression is associated with the basal/triple-negative subtype and is a prognostic marker of poor outcome in patients with breast cancer. CDX-011 (glembatumumab vedotin) is a promising new targeted therapy for patients with metastatic triple-negative breast cancers, a patient population that currently lacks targeted-therapy options.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Carcinoma/diagnóstico , Carcinoma/tratamento farmacológico , Glicoproteínas de Membrana/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/fisiologia , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Carcinoma/genética , Carcinoma/mortalidade , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoconjugados , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Oligopeptídeos/uso terapêutico , Prognóstico , Recidiva , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J Biol Chem ; 279(46): 48246-54, 2004 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-15347674

RESUMO

Histone deacetylase 6 (HDAC6) contains tandem catalytic domains and a ubiquitin-binding zinc finger and displays deacetylase activity toward acetylated microtubules. Here we show that unlike its orthologs from Caenorhabditis elegans, Drosophila, and mouse, human HDAC6 possesses a tetradecapeptide repeat domain located between the second deacetylase domain and the C-terminal ubiquitin-binding motif. Related to this structural difference, the cytoplasmic localization of human, but not murine, HDAC6 is resistant to treatment with leptomycin B (LMB). Although it is dispensable for the deacetylase and ubiquitin binding activities of human HDAC6, the tetradecapeptide repeat domain displays acetyl-microtubule targeting ability. Moreover, it forms a unique structure and is required for the LMB-resistant cytoplasmic localization of human HDAC6. Besides the tetradecapeptide repeat domain, human HDAC6 possesses two LMB-sensitive nuclear export signals and a nuclear localization signal. These results thus indicate that the cytoplasmic localization for murine and human HDAC6 proteins is differentially regulated and suggest that the tetradecapeptide repeat domain serves as an important sequence element to stably retain human HDAC6 in the cytoplasm.


Assuntos
Sequência de Aminoácidos , Citoplasma/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Transporte Ativo do Núcleo Celular/fisiologia , Animais , Linhagem Celular , Ácidos Graxos Insaturados/metabolismo , Desacetilase 6 de Histona , Histona Desacetilases/química , Humanos , Camundongos , Dados de Sequência Molecular , Peso Molecular , Sinais de Localização Nuclear , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Alinhamento de Sequência , Tubulina (Proteína)/metabolismo , Ubiquitina/metabolismo , Dedos de Zinco
16.
Mol Cell ; 11(1): 139-50, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12535528

RESUMO

LCoR (ligand-dependent corepressor) is a transcriptional corepressor widely expressed in fetal and adult tissues that is recruited to agonist-bound nuclear receptors through a single LXXLL motif. LCoR binding to estrogen receptor alpha depends in part on residues in the coactivator binding pocket distinct from those bound by TIF-2. Repression by LCoR is abolished by histone deacetylase inhibitor trichostatin A in a receptor-dependent fashion, indicating HDAC-dependent and -independent modes of action. LCoR binds directly to specific HDACs in vitro and in vivo. Moreover, LCoR functions by recruiting C-terminal binding protein corepressors through two consensus binding motifs and colocalizes with CtBPs in the nucleus. LCoR represents a class of corepressor that attenuates agonist-activated nuclear receptor signaling by multiple mechanisms.


Assuntos
Histona Desacetilases/metabolismo , Proteínas Repressoras/metabolismo , Adulto , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Sítios de Ligação , Células COS , Inibidores Enzimáticos/metabolismo , Receptor alfa de Estrogênio , Feto/fisiologia , Genes Reporter , Inibidores de Histona Desacetilases , Histona Desacetilases/genética , Humanos , Ácidos Hidroxâmicos/metabolismo , Hibridização In Situ , Ligantes , Dados de Sequência Molecular , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Coativador 2 de Receptor Nuclear , Placenta/citologia , Placenta/fisiologia , Ligação Proteica , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Repressoras/química , Proteínas Repressoras/genética , Alinhamento de Sequência , Fatores de Transcrição/metabolismo , Ativação Transcricional , Células Tumorais Cultivadas , Técnicas do Sistema de Duplo-Híbrido
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