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1.
Stem Cells ; 39(3): 296-305, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33438789

RESUMO

Skeletal progenitor/stem cells (SSCs) play a critical role in postnatal bone growth and maintenance. Telomerase (Tert) activity prevents cellular senescence and is required for maintenance of stem cells in self-renewing tissues. Here we investigated the role of mTert-expressing cells in postnatal mouse long bone and found that mTert expression is enriched at the time of adolescent bone growth. mTert-GFP+ cells were identified in regions known to house SSCs, including the metaphyseal stroma, growth plate, and the bone marrow. We also show that mTert-expressing cells are a distinct SSC population with enriched colony-forming capacity and contribute to multiple mesenchymal lineages, in vitro. In contrast, in vivo lineage-tracing studies identified mTert+ cells as osteochondral progenitors and contribute to the bone-forming cell pool during endochondral bone growth with a subset persisting into adulthood. Taken together, our results show that mTert expression is temporally regulated and marks SSCs during a discrete phase of transitional growth between rapid bone growth and maintenance.


Assuntos
Células Epiteliais/metabolismo , Células-Tronco/metabolismo , Telomerase/metabolismo , Animais , Medula Óssea/metabolismo , Ciclo Celular/fisiologia , Proliferação de Células/fisiologia , Senescência Celular/fisiologia , Camundongos
2.
Nat Struct Mol Biol ; 30(1): 10-21, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36522426

RESUMO

The mechanism controlling the dynamic targeting of SWI/SNF has long been postulated to be coordinated by transcription factors (TFs), yet demonstrating a specific TF influence has proven difficult. Here we take a multi-omics approach to interrogate transient SWI/SNF interactors, chromatin targeting and the resulting three-dimensional epigenetic landscape. We utilize the labeling technique TurboID to map the SWI/SNF interactome and identify the activator protein-1 (AP-1) family members as critical interacting partners for SWI/SNF complexes. CUT&RUN profiling demonstrates SWI/SNF targeting enrichment at AP-1 bound loci, as well as SWI/SNF-AP-1 cooperation in chromatin targeting. HiChIP reveals AP-1-SWI/SNF-dependent restructuring of the three-dimensional promoter-enhancer architecture and generation of enhancer hubs. Through interrogation of the SWI/SNF-AP-1 interaction, we demonstrate an SWI/SNF dependency on AP-1-mediated chromatin localization. We propose that pioneer factors, such as AP-1, bind and target SWI/SNF to inactive chromatin, where it restructures the genomic landscape into an active state through epigenetic rewiring spanning multiple dimensions.


Assuntos
Cromatina , Fator de Transcrição AP-1 , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Montagem e Desmontagem da Cromatina , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas
3.
PLoS One ; 17(8): e0272771, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36018850

RESUMO

MYC is one of the most dysregulated oncogenes and is thought to be fundamental to tumor formation and/or maintenance in many cancer types. This dominant pro-tumor activity makes MYC an attractive target for cancer therapy. However, MYC is a transcription factor lacking enzymatic activity, and the structure of one of its two domains is unknown e.g., its transactivation domain. Consequently, few direct MYC-targeting therapies have been developed, and none have been successful in the clinic. Nevertheless, significant effort has been devoted to understanding the mechanisms of oncogenic MYC activity with the objective of uncovering novel vulnerabilities of MYC-dependent cancers. These extensive investigations have revealed in detail how MYC translocation, amplification, and other upstream perturbations contribute to MYC activity in cancer. However, missense mutations of the MYC gene have remained relatively understudied for their potential role in MYC-mediated oncogenesis. While the function of several low-frequency mutations in MYC have been described, our understanding of other equally or more frequent mutations is incomplete. Herein, we define the function of a recurrent missense mutation in MYC resulting in the substitution S146L. This mutation enhances the interaction between MYC and its cofactor TRRAP and may enhance oncogenic MYC activity in certain cellular contexts.


Assuntos
Neoplasias , Proteínas Proto-Oncogênicas c-myc , Humanos
4.
Stem Cell Reports ; 10(1): 17-26, 2018 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-29276155

RESUMO

The intestinal epithelium serves as an essential barrier to the outside world and is maintained by functionally distinct populations of rapidly cycling intestinal stem cells (CBC ISCs) and slowly cycling, reserve ISCs (r-ISCs). Because disruptions in the epithelial barrier can result from pathological activation of the immune system, we sought to investigate the impact of inflammation on ISC behavior during the regenerative response. In a murine model of αCD3 antibody-induced small-intestinal inflammation, r-ISCs proved highly resistant to injury, while CBC ISCs underwent apoptosis. Moreover, r-ISCs were induced to proliferate and functionally contribute to intestinal regeneration. Further analysis revealed that the inflammatory cytokines interferon gamma and tumor necrosis factor alpha led to r-ISC activation in enteroid culture, which could be blocked by the JAK/STAT inhibitor, tofacitinib. These results highlight an important role for r-ISCs in response to acute intestinal inflammation and show that JAK/STAT-1 signaling is required for the r-ISC regenerative response.


Assuntos
Enterite/metabolismo , Mucosa Intestinal/fisiologia , Intestino Delgado/metabolismo , Janus Quinases/metabolismo , Regeneração , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Células-Tronco/metabolismo , Doença Aguda , Animais , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Enterite/induzido quimicamente , Enterite/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Mucosa Intestinal/patologia , Intestino Delgado/patologia , Janus Quinases/antagonistas & inibidores , Camundongos , Camundongos Transgênicos , Piperidinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Fator de Transcrição STAT1/antagonistas & inibidores , Células-Tronco/patologia
5.
Cell Rep ; 13(11): 2403-2411, 2015 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-26686631

RESUMO

The cellular and molecular mechanisms underlying adaptive changes to physiological stress within the intestinal epithelium remain poorly understood. Here, we show that PTEN, a negative regulator of the PI3K→AKT→mTORC1-signaling pathway, is an important regulator of dormant intestinal stem cells (d-ISCs). Acute nutrient deprivation leads to transient PTEN phosphorylation within d-ISCs and a corresponding increase in their number. This release of PTEN inhibition renders d-ISCs functionally poised to contribute to the regenerative response during re-feeding via cell-autonomous activation of the PI3K→AKT→mTORC1 pathway. Consistent with its role in mediating cell survival, PTEN is required for d-ISC maintenance at baseline, and intestines lacking PTEN have diminished regenerative capacity after irradiation. Our results highlight a PTEN-dependent mechanism for d-ISC maintenance and further demonstrate the role of d-ISCs in the intestinal response to stress.


Assuntos
Intestinos/citologia , Estado Nutricional , PTEN Fosfo-Hidrolase/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Animais , Proliferação de Células , Feminino , Genes Reporter , Intestinos/patologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Complexos Multiproteicos/metabolismo , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Telomerase/genética , Telomerase/metabolismo
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