RESUMO
Oncogenic RAS-induced senescence (OIS) is an autonomous tumour suppressor mechanism associated with premalignancy1,2. Achieving this phenotype typically requires a high level of oncogenic stress, yet the phenotype provoked by lower oncogenic dosage remains unclear. Here we develop oncogenic RAS dose-escalation models in vitro and in vivo, revealing a RAS dose-driven non-linear continuum of downstream phenotypes. In a hepatocyte OIS model in vivo, ectopic expression of NRAS(G12V) does not induce tumours, in part owing to OIS-driven immune clearance3. Single-cell RNA sequencing analyses reveal distinct hepatocyte clusters with typical OIS or progenitor-like features, corresponding to high and intermediate levels of NRAS(G12V), respectively. When titred down, NRAS(G12V)-expressing hepatocytes become immune resistant and develop tumours. Time-series monitoring at single-cell resolution identifies two distinct tumour types: early-onset aggressive undifferentiated and late-onset differentiated hepatocellular carcinoma. The molecular signature of each mouse tumour type is associated with different progenitor features and enriched in distinct human hepatocellular carcinoma subclasses. Our results define the oncogenic dosage-driven OIS spectrum, reconciling the senescence and tumour initiation phenotypes in early tumorigenesis.
RESUMO
Musculoskeletal diseases such as muscular dystrophy, cachexia, osteoarthritis, and rheumatoid arthritis impair overall physical health and reduce survival. Patients suffer from pain, dysfunction, and dysmobility due to inflammation and fibrosis in bones, muscles, and joints, both locally and systemically. The Interleukin-6 (IL-6) family of cytokines, most notably IL-6, is implicated in musculoskeletal disorders and cachexia. Here we show elevated circulating levels of OSM in murine pancreatic cancer cachexia and evaluate the effects of the IL-6 family member, Oncostatin M (OSM), on muscle and bone using adeno-associated virus (AAV) mediated over-expression of murine OSM in wildtype and IL-6 deficient mice. Initial studies with high titer AAV-OSM injection yielded high circulating OSM and IL-6, thrombocytosis, inflammation, and 60% mortality without muscle loss within 4 days. Subsequently, to mimic OSM levels in cachexia, a lower titer of AAV-OSM was used in wildtype and Il6 null mice, observing effects out to 4 weeks and 12 weeks. AAV-OSM caused muscle atrophy and fibrosis in the gastrocnemius, tibialis anterior, and quadriceps of the injected limb, but these effects were not observed on the non-injected side. In contrast, OSM induced both local and distant trabecular bone loss as shown by reduced bone volume, trabecular number, and thickness, and increased trabecular separation. OSM caused cardiac dysfunction including reduced ejection fraction and reduced fractional shortening. RNA-sequencing of cardiac muscle revealed upregulation of genes related to inflammation and fibrosis. None of these effects were different in IL-6 knockout mice. Thus, OSM induces local muscle atrophy, systemic bone loss, tissue fibrosis, and cardiac dysfunction independently of IL-6, suggesting a role for OSM in musculoskeletal conditions with these characteristics, including cancer cachexia.
Assuntos
Cardiopatias , Interleucina-6 , Animais , Caquexia , Fibrose , Inflamação , Interleucina-6/farmacologia , Camundongos , Camundongos Knockout , Atrofia Muscular , Oncostatina M/farmacologia , RNARESUMO
Senescence is a stress-responsive form of stable cell cycle exit. Senescent cells have a distinct gene expression profile, which is often accompanied by the spatial redistribution of heterochromatin into senescence-associated heterochromatic foci (SAHFs). Studying a key component of the nuclear lamina lamin B1 (LMNB1), we report dynamic alterations in its genomic profile and their implications for SAHF formation and gene regulation during senescence. Genome-wide mapping reveals that LMNB1 is depleted during senescence, preferentially from the central regions of lamina-associated domains (LADs), which are enriched for Lys9 trimethylation on histone H3 (H3K9me3). LMNB1 knockdown facilitates the spatial relocalization of perinuclear H3K9me3-positive heterochromatin, thus promoting SAHF formation, which could be inhibited by ectopic LMNB1 expression. Furthermore, despite the global reduction in LMNB1 protein levels, LMNB1 binding increases during senescence in a small subset of gene-rich regions where H3K27me3 also increases and gene expression becomes repressed. These results suggest that LMNB1 may contribute to senescence in at least two ways due to its uneven genome-wide redistribution: first, through the spatial reorganization of chromatin and, second, through gene repression.
Assuntos
Senescência Celular/genética , Montagem e Desmontagem da Cromatina/genética , Heterocromatina/metabolismo , Lamina Tipo B/metabolismo , Linhagem Celular , Núcleo Celular/metabolismo , Células Cultivadas , Regulação da Expressão Gênica , Heterocromatina/química , Histonas/metabolismo , Lamina Tipo B/genética , Ligação Proteica , Estrutura Terciária de ProteínaRESUMO
As a stress response, senescence is a dynamic process involving multiple effector mechanisms whose combination determines the phenotypic quality. Here we identify autophagy as a new effector mechanism of senescence. Autophagy is activated during senescence and its activation is correlated with negative feedback in the PI3K-mammalian target of rapamycin (mTOR) pathway. A subset of autophagy-related genes are up-regulated during senescence: Overexpression of one of those genes, ULK3, induces autophagy and senescence. Furthermore, inhibition of autophagy delays the senescence phenotype, including senescence-associated secretion. Our data suggest that autophagy, and its consequent protein turnover, mediate the acquisition of the senescence phenotype.
Assuntos
Envelhecimento/fisiologia , Autofagia/fisiologia , Mitose/fisiologia , Retroalimentação Fisiológica/fisiologia , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Proteínas Associadas aos Microtúbulos/metabolismo , Neoplasias/fisiopatologia , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Serina-Treonina Quinases TORRESUMO
Autophagy, one of two major intracellular degradation pathways, plays a critical role in energy homeostasis and the quality control of macromolecules and intracellular organelles. Previous work has demonstrated the importance of autophagy in maintaining cellular fitness, both in healthy and stressful conditions, revealing the complex interplay between autophagy and other stress-responsive phenotypes. The complex outcomes of stress-responsive autophagy confer on it both pro- and anti-tumourigenic roles, depending on the cellular and environmental context. Furthermore, recent findings that functionally link autophagy to the tumour suppressor mechanism, cellular senescence, have revealed a new role of autophagy in cancer biology. In this review we summarise the current evidence on the relationship between autophagy and cancer, with a focus on its role in senescence.
Assuntos
Autofagia , Neoplasias/patologia , Humanos , Neoplasias/imunologiaRESUMO
BACKGROUND: Anterior cruciate ligament (ACL) injury rates continue to rise among youth involved in recreational and competitive athletics, requiring a better understanding of how the knee structurally and mechanically responds to activity during musculoskeletal growth. Little is understood about how anatomical risk factors for ACL injury (e.g., small ACL size, narrow intercondylar notch, and steep posterior tibial slope) develop and respond to increased physical activity throughout growth. We hypothesized that the ACL-complex of mice engaged in moderate to strenuous physical activity (i.e., endurance running) throughout late adolescence and young adulthood would positively functionally adapt to repetitive load perturbations. METHODS: Female C57BL6/J mice (8 weeks of age) were either provided free access to a standard cage wheel with added resistance (n = 18) or normal cage activity (n = 18), for a duration of 4 weeks. Daily distance ran, weekly body and food weights, and pre- and post-study body composition measures were recorded. At study completion, muscle weights, three-dimensional knee morphology, ACL cross-sectional area, and ACL mechanical properties of runners and nonrunners were quantified. Statistical comparisons between runners and nonrunners were assessed using a two-way analysis of variance and a Tukey multiple comparisons test, with body weight included as a covariate. RESULTS: Runners had larger quadriceps (p = 0.02) and gastrocnemius (p = 0.05) muscles, but smaller hamstring (p = 0.05) muscles, compared to nonrunners. Though there was no significant difference in ACL size (p = 0.24), it was 13% stronger in runners (p = 0.03). Additionally, both the posterior medial and lateral tibial slopes were 1.2 to 2.2 degrees flatter than those of nonrunners (p < 0.01). CONCLUSIONS: Positive functional adaptations of the knee joint to moderate to strenuous exercise in inbred mice offers hope that that some anatomical risk factors for ACL injury may be reduced through habitual physical activity. However, confirmation that a similar response to loading occurs in humans is needed.
RESUMO
BACKGROUND: Cachexia is frequent, deadly, and untreatable for patients with pancreatic ductal adenocarcinoma (PDAC). The reproductive hormone and cytokine Activin is a mediator of PDAC cachexia, and Activin receptor targeting was clinically tested for cancer cachexia therapy. However, sex-specific manifestations and mechanisms are poorly understood, constraining development of effective treatments. METHODS: Cachexia phenotypes, muscle gene/protein expression, and effects of the Activin blocker ACVR2B/Fc were assessed in LSL-KrasG12D/+ , LSL-Trp53R172H/+ , and Pdx-1-Cre (KPC) mice with autochthonic PDAC. Effects of PDAC and sex hormones were modelled by treating C2C12 myotubes with KPC-cell conditioned medium (CM) and estradiol. Muscle gene expression by RNAseq and change in muscle from serial CT scans were measured in patients with PDAC. RESULTS: Despite equivalent tumour latency (median 17 weeks) and mortality (24.5 weeks), male KPC mice showed earlier and more severe cachexia than females. In early PDAC, male gastrocnemius, quadriceps, and tibialis anterior muscles were reduced (-21.7%, -18.9%, and -20.8%, respectively, all P < 0.001), with only gastrocnemius reduced in females (-16%, P < 0.01). Sex differences disappeared in late PDAC. Plasma Activin A was similarly elevated between sexes throughout, while oestrogen and testosterone levels suggested a virilizing effect of PDAC in females. Estradiol partially protected myotubes from KPC-CM induced atrophy and promoted expression of the potential Activin inhibitor Fstl1. Early-stage female mice showed greater muscle expression of Activin inhibitors Fst, Fstl1, and Fstl3; this sex difference disappeared by late-stage PDAC. ACVR2B/Fc initiated in early PDAC preserved muscle and fat only in male KPC mice, with increases of 41.2%, 52.6%, 39.3%, and 348.8%, respectively, in gastrocnemius, quadriceps, tibialis, and fat pad weights vs. vehicle controls, without effect on tumour. No protection was observed in females. At protein and RNA levels, pro-atrophy pathways were induced more strongly in early-stage males, with sex differences less evident in late-stage disease. As with mass, ACVR2B/Fc blunted atrophy-associated pathways only in males. In patients with resectable PDAC, muscle expression of Activin inhibitors FSTL1, FSLT3, and WFIKKN2/GASP2 were higher in women than men. Overall, among 124 patients on first-line gemcitabine/nab-paclitaxel for PDAC, only men displayed muscle loss (P < 0.001); average muscle wasting in men was greater (-6.63 ± 10.70% vs. -1.62 ± 12.00% mean ± SD, P = 0.038) and more rapid (-0.0098 ± 0.0742%/day vs. -0.0466 ± 0.1066%/day, P = 0.017) than in women. CONCLUSIONS: Pancreatic ductal adenocarcinoma cachexia displays sex-specific phenotypes in mice and humans, with Activin a preferential driver of muscle wasting in males. Sex is a major modulator of cachexia mechanisms. Consideration of sexual dimorphism is essential for discovery and development of effective treatments.
Assuntos
Ativinas , Adenocarcinoma , Carcinoma Ductal Pancreático , Proteínas Relacionadas à Folistatina , Neoplasias Pancreáticas , Ativinas/metabolismo , Adenocarcinoma/complicações , Animais , Caquexia/metabolismo , Carcinoma Ductal Pancreático/complicações , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Estradiol/metabolismo , Estradiol/farmacologia , Feminino , Proteínas Relacionadas à Folistatina/genética , Proteínas Relacionadas à Folistatina/metabolismo , Proteínas Relacionadas à Folistatina/farmacologia , Humanos , Masculino , Camundongos , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Fenótipo , Fatores Sexuais , Neoplasias PancreáticasRESUMO
Both senescence and autophagy have been strongly linked to aging and also cancer development. Numerous molecular, cellular, and physiological changes are known to correlate with an increasing age, yet our understanding of what underlies these changes or how they combine to give rise to the various pathologies associated with aging is still unclear. Levels of autophagy activity are known to decrease with advancing age, in a variety of organisms including mammals. Whereas senescent cells are known to accumulate in our bodies with age. Herein we review evidence from some elegant genetic mouse models linking senescence and also autophagy to aging and cancer. It is especially interesting to note the convergence in the pathological phenotypes of these two processes, senescence and autophagy, in these mouse models.
Assuntos
Envelhecimento/patologia , Autofagia/fisiologia , Senescência Celular/fisiologia , Envelhecimento/fisiologia , Animais , Modelos Animais de Doenças , Humanos , CamundongosRESUMO
Autophagy is an important cellular degradation pathway with a central role in metabolism as well as basic quality control, two processes inextricably linked to ageing. A decrease in autophagy is associated with increasing age, yet it is unknown if this is causal in the ageing process, and whether autophagy restoration can counteract these ageing effects. Here we demonstrate that systemic autophagy inhibition induces the premature acquisition of age-associated phenotypes and pathologies in mammals. Remarkably, autophagy restoration provides a near complete recovery of morbidity and a significant extension of lifespan; however, at the molecular level this rescue appears incomplete. Importantly autophagy-restored mice still succumb earlier due to an increase in spontaneous tumour formation. Thus, our data suggest that chronic autophagy inhibition confers an irreversible increase in cancer risk and uncovers a biphasic role of autophagy in cancer development being both tumour suppressive and oncogenic, sequentially.
Assuntos
Envelhecimento/fisiologia , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Longevidade/fisiologia , Neoplasias , Envelhecimento/genética , Animais , Autofagia/genética , Proteína 5 Relacionada à Autofagia/genética , Transplante de Medula Óssea , Modelos Animais de Doenças , Feminino , Inflamação , Longevidade/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculos , Fenótipo , Proteína Sequestossoma-1/metabolismo , Pele/patologiaRESUMO
The occurrence of intersex fish is widespread in the rivers of England and Wales. The extent of intersex in fish populations is believed to be strongly linked to their exposure to steroid estrogens. The present study presents, to our knowledge, the first national, catchment-based risk assessment for steroid estrogens in the world. A graphical information system-based model predicted the concentrations of estradiol (E2), estrone, and ethinylestradiol, which were combined and compared with known biological effect levels to predict the risk of endocrine disruption for 10,313 individual river reaches (21,452 km) receiving effluent from more than 2000 sewage treatment plants serving more than 29 million people. The large scale of this assessment underlines the usefulness of computer-based risk assessment methods. Overall, 61% [corrected] of the modeled reaches (all percentages are in terms of the total river length modeled) in England and Wales were predicted to be not at risk from endocrine disruption (mean concentrations, <1 ng/L E2 equivalents). A large range existed in the percentage of river reaches at risk in the various regions, from 5% in Wales to 67% in the Thames catchment. Important factors influencing this proportion are the population density, particularly their location, and the available dilution. A very small proportion of reaches (approximately 1-3%) were predicted to be at high risk (>10 ng/L E2 equivalents). Many of these high-risk reaches, however, were ditches, which were composed almost entirely of sewage effluent. The model could be applied equally well to any other chemical of concern emanating from the human population that would be impractical to assess by measurement.
Assuntos
Transtornos do Desenvolvimento Sexual/induzido quimicamente , Estrogênios/toxicidade , Medição de Risco , Animais , Inglaterra , Feminino , Masculino , País de GalesRESUMO
Cellular senescence is a widespread stress response and is widely considered to be an alternative cancer therapeutic goal. Unlike apoptosis, senescence is composed of a diverse set of subphenotypes, depending on which of its associated effector programs are engaged. Here we establish a simple and sensitive cell-based prosenescence screen with detailed validation assays. We characterize the screen using a focused tool compound kinase inhibitor library. We identify a series of compounds that induce different types of senescence, including a unique phenotype associated with irregularly shaped nuclei and the progressive accumulation of G1 tetraploidy in human diploid fibroblasts. Downstream analyses show that all of the compounds that induce tetraploid senescence inhibit Aurora kinase B (AURKB). AURKB is the catalytic component of the chromosome passenger complex, which is involved in correct chromosome alignment and segregation, the spindle assembly checkpoint, and cytokinesis. Although aberrant mitosis and senescence have been linked, a specific characterization of AURKB in the context of senescence is still required. This proof-of-principle study suggests that our protocol is capable of amplifying tetraploid senescence, which can be observed in only a small population of oncogenic RAS-induced senescence, and provides additional justification for AURKB as a cancer therapeutic target.
Assuntos
Aurora Quinase B/antagonistas & inibidores , Poliploidia , Inibidores de Proteínas Quinases/farmacologia , Aurora Quinase B/genética , Divisão Celular , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/enzimologia , Núcleo Celular/genética , Senescência Celular/efeitos dos fármacos , Senescência Celular/genética , Segregação de Cromossomos , Citocinese/genética , Células HeLa , Ensaios de Triagem em Larga Escala/métodos , Humanos , Mitose/efeitos dos fármacos , Mitose/genética , Fenótipo , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
Recent EU directives have emphasised the need to understand and limit potential water quality problems within urban river systems. Under certain conditions sediments and contaminants derived from industrial and domestic waste and the urban surface may be expelled into urban rivers via the sewer and drainage system. These discharges may lead to water quality problems within urban catchments. One aspect of water quality is the suspended sediment. This can be directly detrimental to water quality by affecting the habitat for fish and other biota but it is also closely associated with pollutants, such as heavy metals, which may be adsorbed onto the sediments surface. This paper presents a comparative analysis of sediment yields for a small mixed rural/urban catchment, the Bradford Beck in West Yorkshire, over a number of precipitation events. Flow and water quality parameters were monitored at a high temporal resolution at strategic sites within the urban watercourse over a 2-year period. Rainfall was measured at six locations within the catchment. Analysis of discrete rainfall events allowed an understanding of the temporal and spatial variability of sediment transport within the catchment to be developed. The results demonstrated that for individual storms the sediment yields from the urban sub-catchment were generally higher than those from the rural system although the annual yields were comparable. Sediment transport within the urban area, for large events, was dominated by the impact of the Combined Sewer Overflows discharging. Within these events peak suspended sediment concentration, SSC, were generally higher than the rural system. Within smaller events the main sediment source within the urban area was the surface runoff discharging directly to the urban river. Analysis of SSC and discharge relationships illustrated the different sources of sediment for contrasting events. Within the rural system clockwise hysteresis, indicating exhaustion of sediment supply, was noted for larger storms. The high temporal resolution monitoring has enabled a better understanding of sediment dynamics within the Bradford Beck system to be developed. The general conclusions drawn can provide guidance for addressing sediment related water quality issued in other urban systems.
RESUMO
The core aspect of the senescent phenotype is a stable state of cell cycle arrest. However, this is a disguise that conceals a highly active metabolic cell state with diverse functionality. Both the cell-autonomous and the non-cell-autonomous activities of senescent cells create spatiotemporally dynamic and context-dependent tissue reactions. For example, the senescence-associated secretory phenotype (SASP) provokes not only tumour-suppressive but also tumour-promoting responses. Senescence is now increasingly considered to be an integrated and widespread component that is potentially important for tumour development, tumour suppression and the response to therapy.
Assuntos
Senescência Celular , Neoplasias/etiologia , Animais , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Lesões Pré-Cancerosas/etiologia , Lesões Pré-Cancerosas/patologia , Transdução de Sinais , Microambiente TumoralRESUMO
The process of cellular senescence generates a repressive chromatin environment, however, the role of histone variants and histone proteolytic cleavage in senescence remains unclear. Here, using models of oncogene-induced and replicative senescence, we report novel histone H3 tail cleavage events mediated by the protease Cathepsin L. We find that cleaved forms of H3 are nucleosomal and the histone variant H3.3 is the preferred cleaved form of H3. Ectopic expression of H3.3 and its cleavage product (H3.3cs1), which lacks the first 21 amino acids of the H3 tail, is sufficient to induce senescence. Further, H3.3cs1 chromatin incorporation is mediated by the HUCA histone chaperone complex. Genome-wide transcriptional profiling revealed that H3.3cs1 facilitates transcriptional silencing of cell cycle regulators including RB/E2F target genes, likely via the permanent removal of H3K4me3. Collectively, our study identifies histone H3.3 and its proteolytically processed forms as key regulators of cellular senescence.
Assuntos
Senescência Celular/fisiologia , Histonas/fisiologia , Catepsina L/metabolismo , Ciclo Celular/fisiologia , Cromatina/metabolismo , Cromatina/fisiologia , Fatores de Transcrição E2F/metabolismo , Expressão Ectópica do Gene/fisiologia , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Histonas/metabolismo , Humanos , Melanócitos/metabolismo , Melanócitos/fisiologia , Nucleossomos/metabolismo , Nucleossomos/fisiologia , Proteólise , Proteínas Repressoras/metabolismo , Proteínas Repressoras/fisiologiaRESUMO
It has been 50 years since cellular senescence was first described in human diploid fibroblasts (HDFs), yet its mechanism as well as its physiological and clinical implications are still not fully appreciated. Recent progress suggests that cellular senescence is a collective phenotype, composed of complex networks of effector programs. The balance and quality within the effector network varies depending on the cell type, the nature of the stress as well as the context. Therefore, understanding each of these effectors in the context of the whole network will be necessary in order to fully understand senescence as a whole. Furthermore, searching for new effector programs of senescence will help to define this heterogeneous and complex phenotype according to cellular contexts.
Assuntos
Senescência Celular , Fenótipo , Animais , Autofagia , Regulação da Expressão Gênica , Humanos , Transcrição Gênica/genética , Proteínas ras/metabolismoRESUMO
Evidence for a connection between lysosomes and mTOR is emerging. Seminal work from the Sabatini laboratory has shown that mTOR can be recruited to the lysosomal surface in response to amino acids, in a Rag GTPase-dependent manner, to become activated by Rheb. However the biological significance of this is not fully understood. Recent work from our laboratory has shown that lysosomes spatially link mTOR and autophagy forming a cytoplasmic compartment in close proximity to the Golgi apparatus (GA) during oncogenic Ras-induced senescence. The TOR-autophagy spatial coupling compartment (TASCC) is enriched for autolysosomes, but largely excludes autophagosomes. Our data suggest that mTOR, which is a positive regulator of protein synthesis, is recruited, in part, by the amino acid-rich environment surrounding the autolysosomes. This then facilitates protein synthesis at the nearby rER-GA system, reinforcing lysosome and autophagy biogenesis. Proper TASCC formation contributes to the production of secretory proteins, which also utilizes the rER-GA system. Since mTOR inhibits autophagy during the initial stages of autophagosome formation, TASCC formation is likely to facilitate autophagy by sequestering mTOR, suggesting that the TASCC is a self-enhancing structure.
Assuntos
Autofagia , Senescência Celular , Serina-Treonina Quinases TOR/metabolismo , Compartimento Celular , Fibroblastos/citologia , Fibroblastos/metabolismo , Complexo de Golgi/metabolismo , Humanos , Lisossomos/metabolismo , Fatores de TempoRESUMO
Protein synthesis and autophagic degradation are regulated in an opposite manner by mammalian target of rapamycin (mTOR), whereas under certain conditions it would be beneficial if they occurred in unison to handle rapid protein turnover. We observed a distinct cellular compartment at the trans side of the Golgi apparatus, the TOR-autophagy spatial coupling compartment (TASCC), where (auto)lysosomes and mTOR accumulated during Ras-induced senescence. mTOR recruitment to the TASCC was amino acid- and Rag guanosine triphosphatase-dependent, and disruption of mTOR localization to the TASCC suppressed interleukin-6/8 synthesis. TASCC formation was observed during macrophage differentiation and in glomerular podocytes; both displayed increased protein secretion. The spatial coupling of cells' catabolic and anabolic machinery could augment their respective functions and facilitate the mass synthesis of secretory proteins.
Assuntos
Autofagia , Senescência Celular , Vesículas Citoplasmáticas/metabolismo , Proteínas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Aminoácidos/metabolismo , Animais , Linhagem Celular , Citoplasma/metabolismo , Vesículas Citoplasmáticas/ultraestrutura , Retículo Endoplasmático Rugoso/ultraestrutura , Genes ras , Complexo de Golgi/ultraestrutura , Células HL-60 , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Lisossomos/metabolismo , Lisossomos/ultraestrutura , Camundongos , Proteínas Monoméricas de Ligação ao GTP/genética , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Nocodazol/farmacologia , Fagossomos/metabolismo , Fagossomos/ultraestrutura , Fenótipo , Podócitos/metabolismo , Podócitos/ultraestrutura , Biossíntese de Proteínas , Vacúolos/ultraestrutura , Rede trans-Golgi/metabolismo , Rede trans-Golgi/ultraestruturaRESUMO
Oncogenic stress triggers a range of intracellular protective responses including DNA damage checkpoints, senescence and apoptosis, depending on the cell type and the severity of the particular stress. Senescent cells are metabolically viable but are stably arrested. Senescence is a collective phenotype, however, that is comprised of various signaling pathways and effector mechanisms. Thus, to understand and manipulate the senescence phenotype, it is critical to find its effector mechanisms and determine the relationships between them. We have recently found that autophagy is activated upon acute induction of senescence and facilitates another effector mechanism: the senescence associated secretory phenotype (SASP).
Assuntos
Autofagia/fisiologia , Senescência Celular/fisiologia , Oncogenes , Humanos , Proteínas ras/metabolismoRESUMO
Higher-tier environmental risk assessments on "down-the-drain" chemicals in river networks can be conducted using models such as GREAT-ER (Geography-referenced Regional Exposure Assessment Tool for European Rivers). It is important these models are evaluated and their sensitivities to input variables understood. This study had two primary objectives: evaluate GREAT-ER model performance, comparing simulated modelled predictions for LAS (linear alkylbenzene sulphonate) with measured concentrations, for four rivers in the UK, and investigate model sensitivity to input variables. We demonstrate that the GREAT-ER model is very sensitive to variability in river discharges. However it is insensitive to the form of distributions used to describe chemical usage and removal rate in sewage treatment plants (STPs). It is concluded that more effort should be directed towards improving empirical estimates of effluent load and reducing uncertainty associated with usage and removal rates in STPs. Simulations could be improved by incorporating the effect of river depth on dissipation rates.