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1.
Cell ; 187(16): 4150-4175, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39121846

RESUMO

Cellular senescence is a cell fate triggered in response to stress and is characterized by stable cell-cycle arrest and a hypersecretory state. It has diverse biological roles, ranging from tissue repair to chronic disease. The development of new tools to study senescence in vivo has paved the way for uncovering its physiological and pathological roles and testing senescent cells as a therapeutic target. However, the lack of specific and broadly applicable markers makes it difficult to identify and characterize senescent cells in tissues and living organisms. To address this, we provide practical guidelines called "minimum information for cellular senescence experimentation in vivo" (MICSE). It presents an overview of senescence markers in rodent tissues, transgenic models, non-mammalian systems, human tissues, and tumors and their use in the identification and specification of senescent cells. These guidelines provide a uniform, state-of-the-art, and accessible toolset to improve our understanding of cellular senescence in vivo.


Assuntos
Senescência Celular , Humanos , Animais , Biomarcadores/metabolismo , Guias como Assunto , Neoplasias/patologia
2.
Cell ; 186(2): 233-235, 2023 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-36669469

RESUMO

Reactivation of endogenous retroviruses (ERVs), the relics of ancient infections, has been implicated in a number of disease contexts. In this issue of Cell, Liu et al. show how reactivation of ERVs in old age can induce senescence. This awakening of ERVs is associated with their epigenetic derepression and contributes to age-associated chronic inflammation.


Assuntos
Envelhecimento , Retrovirus Endógenos , Retrovirus Endógenos/genética , Envelhecimento/genética , Envelhecimento/patologia , Inflamação
3.
Cell ; 184(22): 5506-5526, 2021 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-34715021

RESUMO

Endogenous cytoplasmic DNA (cytoDNA) species are emerging as key mediators of inflammation in diverse physiological and pathological contexts. Although the role of endogenous cytoDNA in innate immune activation is well established, the cytoDNA species themselves are often poorly characterized and difficult to distinguish, and their mechanisms of formation, scope of function and contribution to disease are incompletely understood. Here, we summarize current knowledge in this rapidly progressing field with emphases on similarities and differences between distinct cytoDNAs, their underlying molecular mechanisms of formation and function, interactions between cytoDNA pathways, and therapeutic opportunities in the treatment of age-associated diseases.


Assuntos
Envelhecimento/metabolismo , Citoplasma/metabolismo , DNA/metabolismo , Doença , Animais , Humanos , Micronúcleo Germinativo/metabolismo , Retroelementos/genética
4.
Cell ; 179(4): 813-827, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31675495

RESUMO

Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers. We also present a resource tool to facilitate the identification of genes linked with senescence, SeneQuest (available at http://Senequest.net). Lastly, we propose an algorithm to accurately assess and quantify senescence, both in cultured cells and in vivo.


Assuntos
Envelhecimento/genética , Biomarcadores , Senescência Celular/genética , Doenças Genéticas Inatas/genética , Pontos de Checagem do Ciclo Celular/genética , Cromatina/genética , Regulação da Expressão Gênica/genética , Doenças Genéticas Inatas/terapia , Humanos
5.
Cell ; 177(3): 572-586.e22, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-30955884

RESUMO

Drug resistance and relapse remain key challenges in pancreatic cancer. Here, we have used RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and genome-wide CRISPR analysis to map the molecular dependencies of pancreatic cancer stem cells, highly therapy-resistant cells that preferentially drive tumorigenesis and progression. This integrated genomic approach revealed an unexpected utilization of immuno-regulatory signals by pancreatic cancer epithelial cells. In particular, the nuclear hormone receptor retinoic-acid-receptor-related orphan receptor gamma (RORγ), known to drive inflammation and T cell differentiation, was upregulated during pancreatic cancer progression, and its genetic or pharmacologic inhibition led to a striking defect in pancreatic cancer growth and a marked improvement in survival. Further, a large-scale retrospective analysis in patients revealed that RORγ expression may predict pancreatic cancer aggressiveness, as it positively correlated with advanced disease and metastasis. Collectively, these data identify an orthogonal co-option of immuno-regulatory signals by pancreatic cancer stem cells, suggesting that autoimmune drugs should be evaluated as novel treatment strategies for pancreatic cancer patients.


Assuntos
Adenocarcinoma/patologia , Células-Tronco Neoplásicas/metabolismo , Neoplasias Pancreáticas/patologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Animais , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Diferenciação Celular , Epigênese Genética , Biblioteca Gênica , Humanos , Camundongos , Camundongos Knockout , Camundongos SCID , Células-Tronco Neoplásicas/citologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Interleucina-10/antagonistas & inibidores , Receptores de Interleucina-10/genética , Receptores de Interleucina-10/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma , Células Tumorais Cultivadas
6.
Nature ; 630(8016): 475-483, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38839958

RESUMO

Senescence is a cellular state linked to ageing and age-onset disease across many mammalian species1,2. Acutely, senescent cells promote wound healing3,4 and prevent tumour formation5; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. Whereas senescent cells are active targets for anti-ageing therapy6-11, why these cells form in vivo, how they affect tissue ageing and the effect of their elimination remain unclear12,13. Here we identify naturally occurring senescent glia in ageing Drosophila brains and decipher their origin and influence. Using Activator protein 1 (AP1) activity to screen for senescence14,15, we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly lifespan and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally occurring senescent glia in vivo and indicate that these cells link key ageing phenomena: mitochondrial dysfunction and lipid accumulation.


Assuntos
Envelhecimento , Encéfalo , Senescência Celular , Drosophila melanogaster , Metabolismo dos Lipídeos , Mitocôndrias , Neuroglia , Animais , Feminino , Humanos , Masculino , Envelhecimento/metabolismo , Envelhecimento/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/citologia , Drosophila melanogaster/metabolismo , Drosophila melanogaster/citologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Longevidade , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo , Fator de Transcrição AP-1/metabolismo , Lipídeos , Inflamação/metabolismo , Inflamação/patologia
7.
Nature ; 622(7983): 627-636, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37821702

RESUMO

Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.


Assuntos
Apoptose , Senescência Celular , Citosol , DNA Mitocondrial , Mitocôndrias , Animais , Camundongos , Citosol/metabolismo , DNA Mitocondrial/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Necrose Dirigida por Permeabilidade Transmembrânica da Mitocôndria , Estudo de Prova de Conceito , Inflamação/metabolismo , Fenótipo , Longevidade , Envelhecimento Saudável
8.
Genes Dev ; 34(5-6): 428-445, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32001510

RESUMO

Cellular senescence is a potent tumor suppressor mechanism but also contributes to aging and aging-related diseases. Senescence is characterized by a stable cell cycle arrest and a complex proinflammatory secretome, termed the senescence-associated secretory phenotype (SASP). We recently discovered that cytoplasmic chromatin fragments (CCFs), extruded from the nucleus of senescent cells, trigger the SASP through activation of the innate immunity cytosolic DNA sensing cGAS-STING pathway. However, the upstream signaling events that instigate CCF formation remain unknown. Here, we show that dysfunctional mitochondria, linked to down-regulation of nuclear-encoded mitochondrial oxidative phosphorylation genes, trigger a ROS-JNK retrograde signaling pathway that drives CCF formation and hence the SASP. JNK links to 53BP1, a nuclear protein that negatively regulates DNA double-strand break (DSB) end resection and CCF formation. Importantly, we show that low-dose HDAC inhibitors restore expression of most nuclear-encoded mitochondrial oxidative phosphorylation genes, improve mitochondrial function, and suppress CCFs and the SASP in senescent cells. In mouse models, HDAC inhibitors also suppress oxidative stress, CCF, inflammation, and tissue damage caused by senescence-inducing irradiation and/or acetaminophen-induced mitochondria dysfunction. Overall, our findings outline an extended mitochondria-to-nucleus retrograde signaling pathway that initiates formation of CCF during senescence and is a potential target for drug-based interventions to inhibit the proaging SASP.


Assuntos
Núcleo Celular/patologia , Senescência Celular/fisiologia , Cromatina/patologia , Citoplasma/patologia , Mitocôndrias/patologia , Transdução de Sinais , Animais , Núcleo Celular/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Inflamação/fisiopatologia , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo
9.
Mol Cell ; 73(4): 684-698.e8, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30773298

RESUMO

Accumulation of senescent cells during aging contributes to chronic inflammation and age-related diseases. While senescence is associated with profound alterations of the epigenome, a systematic view of epigenetic factors in regulating senescence is lacking. Here, we curated a library of short hairpin RNAs for targeted silencing of all known epigenetic proteins and performed a high-throughput screen to identify key candidates whose downregulation can delay replicative senescence of primary human cells. This screen identified multiple new players including the histone acetyltransferase p300 that was found to be a primary driver of the senescent phenotype. p300, but not the paralogous CBP, induces a dynamic hyper-acetylated chromatin state and promotes the formation of active enhancer elements in the non-coding genome, leading to a senescence-specific gene expression program. Our work illustrates a causal role of histone acetyltransferases and acetylation in senescence and suggests p300 as a potential therapeutic target for senescence and age-related diseases.


Assuntos
Proliferação de Células , Senescência Celular , Montagem e Desmontagem da Cromatina , Cromatina/enzimologia , Fibroblastos/enzimologia , Histonas/metabolismo , Processamento de Proteína Pós-Traducional , Fatores de Transcrição de p300-CBP/metabolismo , Acetilação , Proliferação de Células/genética , Senescência Celular/genética , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Repressão Epigenética , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Histonas/genética , Humanos , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Fatores de Tempo , Transcrição Gênica , Fatores de Transcrição de p300-CBP/genética
10.
Blood ; 143(8): 697-712, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38048593

RESUMO

ABSTRACT: Aberrant expression of stem cell-associated genes is a common feature in acute myeloid leukemia (AML) and is linked to leukemic self-renewal and therapy resistance. Using AF10-rearranged leukemia as a prototypical example of the recurrently activated "stemness" network in AML, we screened for chromatin regulators that sustain its expression. We deployed a CRISPR-Cas9 screen with a bespoke domain-focused library and identified several novel chromatin-modifying complexes as regulators of the TALE domain transcription factor MEIS1, a key leukemia stem cell (LSC)-associated gene. CRISPR droplet sequencing revealed that many of these MEIS1 regulators coordinately controlled the transcription of several AML oncogenes. In particular, we identified a novel role for the Tudor-domain-containing chromatin reader protein SGF29 in the transcription of AML oncogenes. Furthermore, SGF29 deletion impaired leukemogenesis in models representative of multiple AML subtypes in multiple AML subtype models. Our studies reveal a novel role for SGF29 as a nononcogenic dependency in AML and identify the SGF29 Tudor domain as an attractive target for drug discovery.


Assuntos
Proteínas de Homeodomínio , Leucemia Mieloide Aguda , Humanos , Proteínas de Homeodomínio/genética , Cromatina/genética , Fatores de Transcrição/genética , Proteína Meis1/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Carcinogênese
11.
Mol Cell ; 71(6): 882-895, 2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-30241605

RESUMO

Age-associated changes to the mammalian DNA methylome are well documented and thought to promote diseases of aging, such as cancer. Recent studies have identified collections of individual methylation sites whose aggregate methylation status measures chronological age, referred to as the DNA methylation clock. DNA methylation may also have value as a biomarker of healthy versus unhealthy aging and disease risk; in other words, a biological clock. Here we consider the relationship between the chronological and biological clocks, their underlying mechanisms, potential consequences, and their utility as biomarkers and as targets for intervention to promote healthy aging and longevity.


Assuntos
Envelhecimento/genética , Senescência Celular/genética , Metilação de DNA/genética , Animais , Relógios Biológicos/genética , Senescência Celular/fisiologia , Ilhas de CpG/genética , Epigênese Genética/genética , Humanos , Longevidade/genética
12.
J Cell Sci ; 136(16)2023 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-37589340

RESUMO

Autophagy is a recycling mechanism involved in cellular homeostasis with key implications for health and disease. The conjugation of the ATG8 family proteins, which includes LC3B (also known as MAP1LC3B), to autophagosome membranes, constitutes a hallmark of the canonical autophagy process. After ATG8 proteins are conjugated to the autophagosome membranes via lipidation, they orchestrate a plethora of protein-protein interactions that support key steps of the autophagy process. These include binding to cargo receptors to allow cargo recruitment, association with proteins implicated in autophagosome transport and autophagosome-lysosome fusion. How these diverse and critical protein-protein interactions are regulated is still not well understood. Recent reports have highlighted crucial roles for post-translational modifications of ATG8 proteins in the regulation of ATG8 functions and the autophagy process. This Review summarizes the main post-translational regulatory events discovered to date to influence the autophagy process, mostly described in mammalian cells, including ubiquitylation, acetylation, lipidation and phosphorylation, as well as their known contributions to the autophagy process, physiology and disease.


Assuntos
Autofagia , Processamento de Proteína Pós-Traducional , Animais , Família da Proteína 8 Relacionada à Autofagia/genética , Fosforilação , Autofagossomos , Mamíferos
13.
EMBO Rep ; 24(10): e57927, 2023 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-37650879

RESUMO

Epigenetic modifications are known to be crucial for hematopoietic stem cell (HSC) differentiation, with the BET family member BRD4 playing a vital role in this as an epigenetic reader. In this issue of EMBO reports, Yang et al (2023) demonstrate that the absence of BRD4 leads to senescence in HSCs and hematopoietic progenitor cells (HPCs), affecting the expression of crucial genes involved in myeloid and erythroid development. These data suggest that BRD4 has a protective role in preserving histone tails, thereby sustaining normal HSC/HPC functions.

16.
Biophys J ; 2024 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-39039794

RESUMO

It is important to understand the behaviors of fluorescent molecules because, firstly, they are often utilized as probes in biophysical experiments and, secondly, they are crucial cofactors in biological processes such as photosynthesis. A phenomenon called "fluorescence quenching" occurs when fluorophores are present at high concentrations, but the mechanisms for quenching are debated. Here, we used a technique called "in-membrane electrophoresis" to generate concentration gradients of fluorophores within a supported lipid bilayer, across which quenching was expected to occur. Fluorescence lifetime imaging microscopy (FLIM) provides images where the fluorescence intensity in each pixel is correlated to fluorescence lifetime: the intensity provides information about the location and concentration of fluorophores and the lifetime reveals the occurrence of energy-dissipative processes. FLIM was used to compare the quenching behavior of three commonly used fluorophores: Texas Red (TR), nitrobenzoaxadiazole (NBD), and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY). FLIM images provided evidence of quenching in regions where the fluorophores accumulated, but the degree of quenching varied between the different fluorophores. The relationship between quenching and concentration was quantified and the "critical radius for trap formation," representing the relative quenching strength, was calculated as 2.70, 2.02, and 1.14 nm, for BODIPY, TR, and NBD, respectively. The experimental data support the theory that quenching takes place via a "transfer-to-trap" mechanism which proposes, firstly, that excitation energy is transferred between fluorophores and may reach a "trap site," resulting in immediate energy dissipation, and, secondly, that trap sites are formed in a concentration-dependent manner. Some previous work suggested that quenching occurs only when fluorophores aggregate, or form long-lived dimers, but our data and this theory argue that traps may be "statistical pairs" of fluorophores that exist only transiently. Our findings should inspire future work to assess whether these traps can be charge-transfer states, excited-state dimers, or something else.

17.
Mol Cell ; 61(2): 210-21, 2016 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-26774282

RESUMO

Crosstalk between cellular metabolism and the epigenome regulates epigenetic and metabolic homeostasis and normal cell behavior. Changes in cancer cell metabolism can directly impact epigenetic regulation and promote transformation. Here we analyzed the contribution of methionine and serine metabolism to methylation of DNA and RNA. Serine can contribute to this pathway by providing one-carbon units to regenerate methionine from homocysteine. While we observed this contribution under methionine-depleted conditions, unexpectedly, we found that serine supported the methionine cycle in the presence and absence of methionine through de novo ATP synthesis. Serine starvation increased the methionine/S-adenosyl methionine ratio, decreasing the transfer of methyl groups to DNA and RNA. While serine starvation dramatically decreased ATP levels, this was accompanied by lower AMP and did not activate AMPK. This work highlights the difference between ATP turnover and new ATP synthesis and defines a vital function of nucleotide synthesis beyond making nucleic acids.


Assuntos
Trifosfato de Adenosina/biossíntese , Metilação de DNA , Metionina/metabolismo , Neoplasias/metabolismo , Serina/metabolismo , Monofosfato de Adenosina/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Metilação de DNA/efeitos dos fármacos , Homocisteína/farmacologia , Humanos , RNA/metabolismo , S-Adenosilmetionina/metabolismo , Estresse Fisiológico/efeitos dos fármacos
18.
Proc Natl Acad Sci U S A ; 118(20)2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-33972419

RESUMO

Agriculture is a major contributor to air pollution, the largest environmental risk factor for mortality in the United States and worldwide. It is largely unknown, however, how individual foods or entire diets affect human health via poor air quality. We show how food production negatively impacts human health by increasing atmospheric fine particulate matter (PM2.5), and we identify ways to reduce these negative impacts of agriculture. We quantify the air quality-related health damages attributable to 95 agricultural commodities and 67 final food products, which encompass >99% of agricultural production in the United States. Agricultural production in the United States results in 17,900 annual air quality-related deaths, 15,900 of which are from food production. Of those, 80% are attributable to animal-based foods, both directly from animal production and indirectly from growing animal feed. On-farm interventions can reduce PM2.5-related mortality by 50%, including improved livestock waste management and fertilizer application practices that reduce emissions of ammonia, a secondary PM2.5 precursor, and improved crop and animal production practices that reduce primary PM2.5 emissions from tillage, field burning, livestock dust, and machinery. Dietary shifts toward more plant-based foods that maintain protein intake and other nutritional needs could reduce agricultural air quality-related mortality by 68 to 83%. In sum, improved livestock and fertilization practices, and dietary shifts could greatly decrease the health impacts of agriculture caused by its contribution to reduced air quality.


Assuntos
Agricultura/normas , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Alimentos/normas , Nível de Saúde , Material Particulado/análise , Agricultura/métodos , Agricultura/estatística & dados numéricos , Amônia/análise , Animais , Produtos Agrícolas/metabolismo , Doença/etiologia , Monitoramento Ambiental/métodos , Monitoramento Ambiental/estatística & dados numéricos , Fertilizantes , Geografia , Humanos , Gado/metabolismo , Mortalidade/tendências , Material Particulado/efeitos adversos , Estados Unidos
19.
Genes Dev ; 30(3): 321-36, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26833731

RESUMO

Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Previous observations link the transcription-associated methyltransferase and oncoprotein MLL1 to the DDR, leading us to investigate the role of MLL1 in SASP expression. Our findings reveal direct MLL1 epigenetic control over proproliferative cell cycle genes: MLL1 inhibition represses expression of proproliferative cell cycle regulators required for DNA replication and DDR activation, thus disabling SASP expression. Strikingly, however, these effects of MLL1 inhibition on SASP gene expression do not impair OIS and, furthermore, abolish the ability of the SASP to enhance cancer cell proliferation. More broadly, MLL1 inhibition also reduces "SASP-like" inflammatory gene expression from cancer cells in vitro and in vivo independently of senescence. Taken together, these data demonstrate that MLL1 inhibition may be a powerful and effective strategy for inducing cancerous growth arrest through the direct epigenetic regulation of proliferation-promoting genes and the avoidance of deleterious OIS- or TIS-related tumor secretomes, which can promote both drug resistance and tumor progression.


Assuntos
Senescência Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Transdução de Sinais/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas de Ciclo Celular/genética , Linhagem Celular , Proliferação de Células , Dano ao DNA , Técnicas de Silenciamento de Genes , Células HEK293 , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Humanos , Inflamação/genética , Células MCF-7 , Proteína de Leucina Linfoide-Mieloide/antagonistas & inibidores , NF-kappa B/metabolismo , Neoplasias/fisiopatologia , Fenótipo
20.
EMBO J ; 38(23): e101982, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31633821

RESUMO

Cellular senescence has been shown to contribute to skin ageing. However, the role of melanocytes in the process is understudied. Our data show that melanocytes are the only epidermal cell type to express the senescence marker p16INK4A during human skin ageing. Aged melanocytes also display additional markers of senescence such as reduced HMGB1 and dysfunctional telomeres, without detectable telomere shortening. Additionally, senescent melanocyte SASP induces telomere dysfunction in paracrine manner and limits proliferation of surrounding cells via activation of CXCR3-dependent mitochondrial ROS. Finally, senescent melanocytes impair basal keratinocyte proliferation and contribute to epidermal atrophy in vitro using 3D human epidermal equivalents. Crucially, clearance of senescent melanocytes using the senolytic drug ABT737 or treatment with mitochondria-targeted antioxidant MitoQ suppressed this effect. In conclusion, our study provides proof-of-concept evidence that senescent melanocytes affect keratinocyte function and act as drivers of human skin ageing.


Assuntos
Envelhecimento/patologia , Atrofia/patologia , Senescência Celular , Melanócitos/patologia , Pele/patologia , Telômero/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/efeitos dos fármacos , Atrofia/induzido quimicamente , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Epiderme/efeitos dos fármacos , Epiderme/patologia , Feminino , Humanos , Masculino , Melanócitos/metabolismo , Pessoa de Meia-Idade , Comunicação Parácrina , Espécies Reativas de Oxigênio/metabolismo , Receptores CXCR4/metabolismo , Pele/metabolismo , Telômero/metabolismo , Adulto Jovem
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