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1.
J Clin Invest ; 128(9): 4132-4147, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-29990311

RESUMO

Cyclin D1 is an oncogene frequently overexpressed in human cancers that has a dual function as cell cycle and transcriptional regulator, although the latter is widely unexplored. Here, we investigated the transcriptional role of cyclin D1 in lymphoid tumor cells with cyclin D1 oncogenic overexpression. Cyclin D1 showed widespread binding to the promoters of most actively transcribed genes, and the promoter occupancy positively correlated with the transcriptional output of targeted genes. Despite this association, the overexpression of cyclin D1 in lymphoid cells led to a global transcriptional downmodulation that was proportional to cyclin D1 levels. This cyclin D1-dependent global transcriptional downregulation was associated with a reduced nascent transcription and an accumulation of promoter-proximal paused RNA polymerase II (Pol II) that colocalized with cyclin D1. Concordantly, cyclin D1 overexpression promoted an increase in the Poll II pausing index. This transcriptional impairment seems to be mediated by the interaction of cyclin D1 with the transcription machinery. In addition, cyclin D1 overexpression sensitized cells to transcription inhibitors, revealing a synthetic lethality interaction that was also observed in primary mantle cell lymphoma cases. This finding of global transcriptional dysregulation expands the known functions of oncogenic cyclin D1 and suggests the therapeutic potential of targeting the transcriptional machinery in cyclin D1-overexpressing tumors.


Assuntos
Ciclina D1/genética , Ciclina D1/metabolismo , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Carcinogênese/genética , Linhagem Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Código das Histonas , Humanos , Modelos Biológicos , Regiões Promotoras Genéticas , RNA Polimerase II/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Genética
2.
Blood ; 132(4): 413-422, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-29769262

RESUMO

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy, but some patients have a very indolent evolution. This heterogeneous course is related, in part, to the different biological characteristics of conventional MCL (cMCL) and the distinct subgroup of leukemic nonnodal MCL (nnMCL). Robust criteria to distinguish these MCL subtypes and additional biological parameters that influence their evolution are not well defined. We describe a novel molecular assay that reliably distinguishes cMCL and nnMCL using blood samples. We trained a 16-gene assay (L-MCL16 assay) on the NanoString platform using 19 purified leukemic samples. The locked assay was applied to an independent cohort of 70 MCL patients with leukemic presentation. The assay assigned 37% of cases to nnMCL and 56% to cMCL. nnMCL and cMCL differed in nodal presentation, lactate dehydrogenase, immunoglobulin heavy chain gene mutational status, management options, genomic complexity, and CDKN2A/ATM deletions, but the proportion with 17p/TP53 aberrations was similar in both subgroups. Sequential samples showed that assay prediction was stable over time. nnMCL had a better overall survival (OS) than cMCL (3-year OS 92% vs 69%; P = .006) from the time of diagnosis and longer time to first treatment. Genomic complexity and TP53/CDKN2A aberrations predicted for shorter OS in the entire series and cMCL, whereas only genomic complexity was associated with shorter time to first treatment and OS in nnMCL. In conclusion, the newly developed assay robustly recognizes the 2 molecular subtypes of MCL in leukemic samples. Its combination with genetic alterations improves the prognostic evaluation and may provide useful biological information for management decisions.


Assuntos
Biomarcadores Tumorais/genética , Leucemia/genética , Leucemia/patologia , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Mutação , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Genômica , Humanos , Leucemia/classificação , Linfoma de Célula do Manto/classificação , Masculino , Prognóstico , Taxa de Sobrevida
3.
Cell Cycle ; 14(4): 510-5, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25665097

RESUMO

The Zuotin-related factor 1, ZRF1, has recently been identified as an epigenetic regulator of gene transcription in stem cells and cancer. During differentiation of human teratocarcinoma cells, ZRF1 promotes transcriptional induction of developmental genes that are repressed by Polycomb complexes. Importantly, ZRF1 has recently been shown to be required for both neural differentiation of embryonic stem cells (ESCs) and for maintenance of neural progenitor cell (NPC) identity. Moreover, a dual role has now emerged for ZRF1 in cancer: on the one hand, ZRF1 plays a crucial role in oncogene-induced senescence (OIS) by activating the INK4/ARF locus, thus working as a tumor suppressor; on the other hand, ZRF1 promotes leukemogenesis in acute myeloid leukemia (AML) in a Polycomb-independent fashion. Therefore, increasing evidence points to ZRF1 as a novel target for therapy of neurodegenerative diseases and cancer.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Células-Tronco Embrionárias/citologia , Epigênese Genética/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Proteínas Oncogênicas/metabolismo , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Senescência Celular/genética , Senescência Celular/fisiologia , Proteínas de Ligação a DNA/genética , Células-Tronco Embrionárias/metabolismo , Epigênese Genética/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Camundongos , Proteínas Oncogênicas/genética , Conformação Proteica
4.
Epigenomics ; 3(5): 567-80, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22126247

RESUMO

The introduction of new methods for genome-wide analyses of the chromatin state, together with the power of refined techniques for mass spectrometry and biochemistry, has provided an unprecedented view on the complexity of eukaryotic gene regulation. Chromatin structure, the state of histone modifications and DNA methylation are highly dynamic and subject to various levels of regulation. In addition, the subunit compositions of the protein complexes that bring about these changes appear to be assembled in a combinatorial manner that is specific for the cell type and developmental stage, providing increased specificity to these complexes. Here we discuss recent evidence regarding the combinatorial control of chromatin regulatory complexes.


Assuntos
Montagem e Desmontagem da Cromatina/fisiologia , Proteínas Cromossômicas não Histona/metabolismo , Metilação de DNA/fisiologia , Histonas/metabolismo , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Fatores de Transcrição/metabolismo , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , DNA Helicases/metabolismo , Humanos , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas do Grupo Polycomb , Proteínas Repressoras/metabolismo
5.
Nat Cell Biol ; 13(12): 1443-9, 2011 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-22020439

RESUMO

MYC proto-oncogene is a key player in cell homeostasis that is commonly deregulated in human carcinogenesis(1). MYC can either activate or repress target genes by forming a complex with MAX (ref. 2). MYC also exerts MAX-independent functions that are not yet fully characterized(3). Cells possess an intrinsic pathway that can abrogate MYC-MAX dimerization and E-box interaction, by inducing phosphorylation of MYC in a PAK2-dependent manner at three residues located in its helix-loop-helix domain(4). Here we show that these carboxy-terminal phosphorylation events switch MYC from an oncogenic to a tumour-suppressive function. In undifferentiated cells, MYC-MAX is targeted to the promoters of retinoic-acid-responsive genes by its direct interaction with the retinoic acid receptor-α (RARα). MYC-MAX cooperates with RARα to repress genes required for differentiation, in an E-box-independent manner. Conversely, on C-terminal phosphorylation of MYC during differentiation, the complex switches from a repressive to an activating function, by releasing MAX and recruiting transcriptional co-activators. Phospho-MYC synergizes with retinoic acid to eliminate circulating leukaemic cells and to decrease the level of tumour invasion. Our results identify an E-box-independent mechanism for transcriptional regulation by MYC that unveils previously unknown functions for MYC in differentiation. These may be exploited to develop alternative targeted therapies.


Assuntos
Elementos E-Box/fisiologia , Regulação Leucêmica da Expressão Gênica/fisiologia , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Transcrição Genética/fisiologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Diferenciação Celular/genética , Células HL-60 , Homeostase/genética , Humanos , Leucemia Promielocítica Aguda/metabolismo , Proteínas Proto-Oncogênicas c-myc/química , Proteínas Proto-Oncogênicas c-myc/metabolismo , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo
6.
Nature ; 468(7327): 1124-8, 2010 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-21179169

RESUMO

Covalent modification of histones is fundamental in orchestrating chromatin dynamics and transcription. One example of such an epigenetic mark is the mono-ubiquitination of histones, which mainly occurs at histone H2A and H2B. Ubiquitination of histone H2A has been implicated in polycomb-mediated transcriptional silencing. However, the precise role of the ubiquitin mark during silencing is still elusive. Here we show in human cell lines that ZRF1 (zuotin-related factor 1) is specifically recruited to histone H2A when it is ubiquitinated at Lys 119 by means of a novel ubiquitin-interacting domain that is located in the evolutionarily conserved zuotin domain. At the onset of differentiation, ZRF1 specifically displaces polycomb-repressive complex 1 (PRC1) from chromatin and facilitates transcriptional activation. A genome-wide mapping of ZRF1, RING1B and H2A-ubiquitin targets revealed its involvement in the regulation of a large set of polycomb target genes, emphasizing the key role ZRF1 has in cell fate decisions. We provide here a model of the molecular mechanism of switching polycomb-repressed genes to an active state.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Inativação Gênica , Proteínas Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Ativação Transcricional , Linhagem Celular Tumoral , Cromatina/metabolismo , Mapeamento Cromossômico , Regulação da Expressão Gênica , Células HEK293 , Histonas/metabolismo , Humanos , Modelos Biológicos , Proteínas do Grupo Polycomb , Células U937 , Ubiquitinas/metabolismo
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