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A quantitative chemiluminescent method for studying replicative and stress-induced premature senescence in cell cultures

BASSANEZE, Vinicius; MIYAKAWA, Ayumi A.; KRIEGER, Jose E.
Fonte: ACADEMIC PRESS INC ELSEVIER SCIENCE Publicador: ACADEMIC PRESS INC ELSEVIER SCIENCE
Tipo: Artigo de Revista Científica
Português
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beta-Galactosidase (beta-Gal) activity is a widely accepted biomarker to detect senescence both in situ and in vitro. A cytochemical assay based on production of a blue-dyed precipitate that results from the cleavage of the chromogenic substrate X-Gal is commonly used. Blue and nonblue cells are counted under the microscope and a semiquantitative percentage of senescent cells can be obtained. Here, we present a quantitative, fast, and easy to use chemiluminescent assay to detect senescence. The Galacton chemiluminescent method used to detect the prokaryotic beta-Gal reporter enzyme in transfection studies was adapted to assay mammalian beta-Gal. The assay showed linear production of luminescence in a time- and cell-number-dependent manner. The chemiluminescent assay showed significant correlation with the cytochemical assay in detecting replicative senescence (Pearson r = 0.8486, p < 0.005). Moreover, the chemiluminescent method (Galacton) also detected stress-induced senescence in cells treated with H2O2 similar to the cytochemical assay (X-Gal) (Galacton: control 25.207.3 +/- 6548.6. H2O, 52,487.4 +/- 16,284.9, p < 0.05; X-Gal: control 41.31 +/- 7.0%, H2O2 92.97 +/- 2.8%, p < 0.01). Thus, our method is well suited to the detection of replicative and stress-induced senescence in cell culture. (C) 2007 Elsevier Inc. All rights reserved.

Reprogramming of replicative senescence in hepatocellular carcinoma-derived cells

Ozturk, Nuri; Erdal, Esra; Mumcuoglu, Mine; Akcali, Kamil C.; Yalcin, Ozden; Senturk, Serif; Arslan-Ergul, Ayca; Gur, Bala; Yulug, Isik; Cetin-Atalay, Rengul; Yakicier, Cengiz; Yagci, Tamer; Tez, Mesut; Ozturk, Mehmet
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Tumor cells have the capacity to proliferate indefinitely that is qualified as replicative immortality. This ability contrasts with the intrinsic control of the number of cell divisions in human somatic tissues by a mechanism called replicative senescence. Replicative immortality is acquired by inactivation of p53 and p16INK4a genes and reactivation of hTERT gene expression. It is unknown whether the cancer cell replicative immortality is reversible. Here, we show the spontaneous induction of replicative senescence in p53-and p16INK4a-deficient hepatocellular carcinoma cells. This phenomenon is characterized with hTERT repression, telomere shortening, senescence arrest, and tumor suppression. SIP1 gene (ZFHX1B) is partly responsible for replicative senescence, because short hairpin RNA-mediated SIP1 inactivation released hTERT repression and rescued clonal hepatocellular carcinoma cells from senescence arrest.

Mating Type Influences Chromosome Loss and Replicative Senescence in Telomerase Deficient Budding Yeast by Dnl4-dependent Telomere Fusion

Meyer, Damon H.; Bailis, Adam M.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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As we age, the majority of our cells gradually lose the capacity to divide because of replicative senescence that results from the inability to replicate the ends of chromosomes. The timing of senescence is dependent on the length of telomeric DNA, which elicits a checkpoint signal when critically short. Critically short telomeres also become vulnerable to deleterious rearrangements, end degradation and telomere-telomere fusions. Here we report a novel role of non-homologous end joining (NHEJ), a pathway of double-strand break (DSB) repair in influencing both the kinetics of replicative senescence and the rate of chromosome loss in telomerase-deficient Saccharomyces cerevisiae. In telomerase-deficient cells, the absence of NHEJ delays replicative senescence, decreases loss of viability during senescence, and suppresses senescence-associated chromosome loss and telomere-telomere fusion. Differences in mating-type gene expression in haploid and diploid cells affect NHEJ function, resulting in distinct kinetics of replicative senescence. These results suggest that the differences in the kinetics of replicative senescence in haploid and diploid telomerase-deficient yeast is determined by changes in NHEJ-dependent telomere fusion, perhaps through the initiation of the breakage-fusion-bridge (BFB) cycle.

CSIG Inhibits PTEN Translation in Replicative Senescence▿

Ma, Liwei; Chang, Na; Guo, Shuzhen; Li, Qian; Zhang, Zongyu; Wang, Wengong; Tong, Tanjun
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
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Using a suppressive subtractive hybridization system, we identified CSIG (cellular senescence-inhibited gene protein; RSL1D1) that was abundant in young human diploid fibroblast cells but declined upon replicative senescence. Overexpression or knockdown of CSIG did not influence p21Cip1 and p16INK4a expressions. Instead, CSIG negatively regulated PTEN and p27Kip1 expressions, in turn promoting cell proliferation. In PTEN-silenced HEK 293 cells and PTEN-deficient human glioblastoma U87MG cells, the effect of CSIG on p27Kip1 expression and cell division was abolished, suggesting that PTEN was required for the role of CSIG on p27Kip1 regulation and cell cycle progression. Investigation into the underlying mechanism revealed that the regulation of PTEN by CSIG was achieved through a translational suppression mechanism. Further study showed that CSIG interacted with PTEN mRNA in the 5′ untranslated region (UTR) and that knockdown of CSIG led to increased luciferase activity of a PTEN 5′ UTR-luciferase reporter. Moreover, overexpression of CSIG significantly delayed the progression of replicative senescence, while knockdown of CSIG expression accelerated replicative senescence. Knockdown of PTEN diminished the effect of CSIG on cellular senescence. Our findings indicate that CSIG acts as a novel regulatory component of replicative senescence...

Polybromo-associated BRG1-associated factor components BRD7 and BAF180 are critical regulators of p53 required for induction of replicative senescence

Burrows, Anna E.; Smogorzewska, Agata; Elledge, Stephen J.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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A variety of tumor-suppressor mechanisms exist to promote genome integrity and organismal survival. One such mechanism is cellular senescence. In response to replicative aging, DNA damage, and oncogenic stimuli, the p53 and Rb pathways are activated to prevent the proliferation of damaged cells by inducing senescence or apoptosis. We have performed a loss-of-function genetic screen in primary human cells to identify components of the senescence machinery. Here we describe BRD7 and BAF180 as unique regulators of replicative senescence in human cells. Both regulate p53 transcriptional activity toward a subset of its target genes required for replicative and oncogenic stress senescence induction, and BRD7 physically interacts with p53. BRD7 is a deletion target in human cancer, suggesting that loss of BRD7 may provide an additional mechanism to antagonize p53 function in cancer cells.

MiRNA Profile Associated with Replicative Senescence, Extended Cell Culture, and Ectopic Telomerase Expression in Human Foreskin Fibroblasts

Bonifacio, Laura N.; Jarstfer, Michael B.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 01/09/2010 Português
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Senescence is a highly regulated process that limits cellular replication by enforcing a G1 arrest in response to various stimuli. Replicative senescence occurs in response to telomeric DNA erosion, and telomerase expression can offset replicative senescence leading to immortalization of many human cells. Limited data exists regarding changes of microRNA (miRNA) expression during senescence in human cells and no reports correlate telomerase expression with regulation of senescence-related miRNAs. We used miRNA microarrays to provide a detailed account of miRNA profiles for early passage and senescent human foreskin (BJ) fibroblasts as well as early and late passage immortalized fibroblasts (BJ-hTERT) that stably express the human telomerase reverse transcriptase subunit hTERT. Selected miRNAs that were differentially expressed in senescence were assayed for expression in quiescent cells to identify miRNAs that are specifically associated with senescence-associated growth arrest. From this group of senescence-associated miRNAs, we confirmed the ability of miR-143 to induce growth arrest after ectopic expression in young fibroblasts. Remarkably, miR-143 failed to induce growth arrest in BJ-hTERT cells. Importantly, the comparison of late passage immortalized fibroblasts to senescent wild type fibroblasts reveals that miR-146a...

Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence

Kortlever, Roderik M.; Higgins, Paul J.; Bernards, René
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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p53 limits the proliferation of primary diploid fibroblasts by inducing a state of growth arrest named replicative senescence — a process which protects against oncogenic transformation and requires integrity of the p53 tumour suppressor pathway1–3. However, little is known about the downstream target genes of p53 in this growth-limiting response. Here, we report that suppression of the p53 target gene encoding plasminogen activator inhibitor-1 (PAI-1) by RNA interference (RNAi) leads to escape from replicative senescence both in primary mouse embryo fibroblasts and primary human BJ fibroblasts. PAI-1 knockdown results in sustained activation of the PI(3)K–PKB–GSK3β pathway and nuclear retention of cyclin D1, consistent with a role for PAI-1 in regulating growth factor signalling. In agreement with this, we find that the PI(3)K–PKB–GSK3β–cyclin D1 pathway is also causally involved in cellular senescence. Conversely, ectopic expression of PAI-1 in proliferating p53-deficient murine or human fibroblasts induces a phenotype displaying all the hallmarks of replicative senescence. Our data indicate that PAI-1 is not merely a marker of senescence, but is both necessary and sufficient for the induction of replicative senescence downstream of p53.

Sustained CD28 Expression Delays Multiple Features of Replicative Senescence in Human CD8 T Lymphocytes

Parish, Stanley T.; Wu, Jennifer E.; Effros, Rita B.
Fonte: Springer US Publicador: Springer US
Tipo: Artigo de Revista Científica
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CD28 costimulatory signal transduction in T lymphocytes is essential for optimal telomerase activity, stabilization of cytokine mRNAs, and glucose metabolism. During aging and chronic infection with HIV-1, there are increased proportions of CD8 T lymphocytes that lack CD28 expression and show additional features of replicative senescence. Moreover, the abundance of these cells correlates with decreased vaccine responsiveness, early mortality in the very old, and accelerated HIV disease progression. Here, we show that sustained expression of CD28, via gene transduction, retards the process of replicative senescence, as evidenced by enhanced telomerase activity, increased overall proliferative potential, and reduced secretion of pro-inflammatory cytokines. Nevertheless, the transduced cultures eventually do reach senescence, which is associated with increased CTLA-4 gene expression and a loss of CD28 cell surface expression. These findings further elucidate the central role of CD28 in the replicative senescence program, and may ultimately lead to novel therapies for diseases associated with replicative senescence.

Polymerase Epsilon Is Required To Maintain Replicative Senescence▿†

Deshpande, Abhyuday M.; Ivanova, Iglika G.; Raykov, Vasil; Xue, Yuan; Maringele, Laura
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /04/2011 Português
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Replicative senescence is a permanent cell cycle arrest in response to extensive telomere shortening. To understand the mechanisms behind a permanent arrest, we screened for factors affecting replicative senescence in budding yeast lacking telomere elongation pathways. Intriguingly, we found that DNA polymerase epsilon (Pol ε) acts synergistically with Exo1 nuclease to maintain replicative senescence. In contrast, the Pol ε-associated checkpoint and replication protein Mrc1 facilitates escape from senescence. To understand this paradox, in which DNA-synthesizing factors cooperate with DNA-degrading factors to maintain arrest, whereas a checkpoint protein opposes arrest, we analyzed the dynamics of double- and single-stranded DNA (ssDNA) at chromosome ends during senescence. We found evidence for cycles of DNA resection, followed by resynthesis. We propose that resection of the shortest telomere, activating a Rad24Rad17-dependent checkpoint pathway, alternates in time with an Mrc1-regulated Pol ε resynthesis of a short, double-stranded chromosome end, which in turn activates a Rad953BP1-dependent checkpoint pathway. Therefore, instead of one type of DNA damage, different types (ssDNA and a double-strand break-like structure) alternate in a “vicious circle...

Role of p16INK4A in Replicative Senescence and DNA Damage-Induced Premature Senescence in p53-Deficient Human Cells

Mirzayans, Razmik; Andrais, Bonnie; Hansen, Gavin; Murray, David
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
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The p16INK4A (hereafter p16) tumor suppressor is encoded by the INK4A/ARF locus which is among the most commonly dysregulated sequences in human cancer. By inhibiting cyclin-dependent kinases, p16 activates the G1-S checkpoint, and this response is often considered to be critical for establishing a senescence-like growth arrest. Not all studies support a universal role for p16 in senescence. Single-cell analysis of noncancerous human fibroblast cultures undergoing senescence as a function of culture age (replicative senescence) has revealed that p16 is not expressed in the majority (>90%) of cells that exhibit features of senescence (e.g., flattened and enlarged morphology coupled with senescence-associated β-galactosidase expression), ruling out a requirement for p16 in this process. In addition, ionizing radiation triggers premature senescence in human cancer cell lines that do not express p16. These observations are made with cells that express wild-type p53, a key mediator of the DNA damage response. In this paper, we examine the growing evidence suggesting a negative regulatory relationship between p16 and p53 and discuss recent reports that implicate a role for p16 in replicative senescence and ionizing radiation-induced premature senescence in human cells that lack wild-type p53 function.

Nek4 Regulates Entry into Replicative Senescence and the Response to DNA Damage in Human Fibroblasts

Nguyen, Christine L.; Possemato, Richard; Bauerlein, Erica L.; Xie, Anyong; Scully, Ralph; Hahn, William C.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /10/2012 Português
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When explanted into culture, normal human cells exhibit a finite number of cell divisions before entering a proliferative arrest termed replicative senescence. To identify genes essential for entry into replicative senescence, we performed an RNA interference (RNAi)-based loss-of-function screen and found that suppression of the Never in Mitosis Gene A (NIMA)-related protein kinase gene NEK4 disrupted timely entry into senescence. NEK4 suppression extended the number of population doublings required to reach replicative senescence in several human fibroblast strains and resulted in decreased transcription of the cyclin-dependent kinase inhibitor p21. NEK4-suppressed cells displayed impaired cell cycle arrest in response to double-stranded DNA damage, and mass spectrometric analysis of Nek4 immune complexes identified a complex containing DNA-dependent protein kinase catalytic subunit [DNA-PK(cs)], Ku70, and Ku80. NEK4 suppression causes defects in the recruitment of DNA-PK(cs) to DNA upon induction of double-stranded DNA damage, resulting in reduced p53 activation and H2AX phosphorylation. Together, these observations implicate Nek4 as a novel regulator of replicative senescence and the response to double-stranded DNA damage.

Saccharomyces cerevisiae as a Model to Study Replicative Senescence Triggered by Telomere Shortening

Teixeira, M. Teresa
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Publicado em 26/04/2013 Português
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In many somatic human tissues, telomeres shorten progressively because of the DNA-end replication problem. Consequently, cells cease to proliferate and are maintained in a metabolically viable state called replicative senescence. These cells are characterized by an activation of DNA damage checkpoints stemming from eroded telomeres, which are bypassed in many cancer cells. Hence, replicative senescence has been considered one of the most potent tumor suppressor pathways. However, the mechanism through which short telomeres trigger this cellular response is far from being understood. When telomerase is removed experimentally in Saccharomyces cerevisiae, telomere shortening also results in a gradual arrest of population growth, suggesting that replicative senescence also occurs in this unicellular eukaryote. In this review, we present the key steps that have contributed to the understanding of the mechanisms underlying the establishment of replicative senescence in budding yeast. As in mammals, signals stemming from short telomeres activate the DNA damage checkpoints, suggesting that the early cellular response to the shortest telomere(s) is conserved in evolution. Yet closer analysis reveals a complex picture in which the apparent single checkpoint response may result from a variety of telomeric alterations expressed in the absence of telomerase. Accordingly...

Adenosine Deaminase Modulation of Telomerase Activity and Replicative Senescence in Human CD8 T Lymphocytes

Parish, Stanley T.; Kim, Sarah; Sekhon, Rekha K.; Wu, Jennifer E.; Kawakatsu, Yukako; Effros, Rita B.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Increased proportions of CD8 T lymphocytes lacking expression of the CD28 costimulatory receptor have been documented during both aging and chronic infection with HIV-1, and their abundance correlates with numerous deleterious clinical outcomes. CD28-negative cells also arise in cell cultures of CD8+CD28+ following multiple rounds of Ag-driven proliferation, reaching the end stage of replicative senescence. The present study investigates the role of a second T cell costimulatory receptor component, adenosine deaminase (ADA), on the process of replicative senescence. We had previously reported that CD28 signaling is required for optimal telomerase upregulation. In this study, we show that the CD8+CD28+ T lymphocytes that are ADA+ have significantly greater telomerase activity than those that do not express ADA and that ADA is progressively lost as cultures progress to senescence. Because ADA converts adenosine to inosine, cells lacking this enzyme might be subject to prolonged exposure to adenosine, which has immunosuppressive effects. Indeed, we show that chronic exposure of CD8 T lymphocytes to exogenous adenosine accelerates the process of replicative senescence, causing a reduction in overall proliferative potential, reduced telomerase activity...

p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes

Mondal, Abdul M.; Horikawa, Izumi; Pine, Sharon R.; Fujita, Kaori; Morgan, Katherine M.; Vera, Elsa; Mazur, Sharlyn J.; Appella, Ettore; Vojtesek, Borivoj; Blasco, Maria A.; Lane, David P.; Harris, Curtis C.
Fonte: American Society for Clinical Investigation Publicador: American Society for Clinical Investigation
Tipo: Artigo de Revista Científica
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Cellular senescence contributes to aging and decline in tissue function. p53 isoform switching regulates replicative senescence in cultured fibroblasts and is associated with tumor progression. Here, we found that the endogenous p53 isoforms Δ133p53 and p53β are physiological regulators of proliferation and senescence in human T lymphocytes in vivo. Peripheral blood CD8+ T lymphocytes collected from healthy donors displayed an age-dependent accumulation of senescent cells (CD28–CD57+) with decreased Δ133p53 and increased p53β expression. Human lung tumor-associated CD8+ T lymphocytes also harbored senescent cells. Cultured CD8+ blood T lymphocytes underwent replicative senescence that was associated with loss of CD28 and Δ133p53 protein. In poorly proliferative, Δ133p53-low CD8+CD28– cells, reconstituted expression of either Δ133p53 or CD28 upregulated endogenous expression of each other, which restored cell proliferation, extended replicative lifespan and rescued senescence phenotypes. Conversely, Δ133p53 knockdown or p53β overexpression in CD8+CD28+ cells inhibited cell proliferation and induced senescence. This study establishes a role for Δ133p53 and p53β in regulation of cellular proliferation and senescence in vivo. Furthermore...

Multiple genetic pathways regulate replicative senescence in telomerase-deficient yeast

Ballew, Bari J.; Lundblad, Victoria
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Most human tissues express low levels of telomerase and undergo telomere shortening and eventual senescence; the resulting limitation on tissue renewal can lead to a wide range of age-dependent pathophysiologies. Increasing evidence indicates that the decline in cell division capacity in cells that lack telomerase can be influenced by numerous genetic factors. Here, we use telomerase-defective strains of budding yeast to probe whether replicative senescence can be attenuated or accelerated by defects in factors previously implicated in handling of DNA termini. We show that the MRX (Mre11-Rad50-Xrs2) complex, as well as negative (Rif2) and positive (Tel1) regulators of this complex, comprise a single pathway that promotes replicative senescence, in a manner that recapitulates how these proteins modulate resection of DNA ends. In contrast, the Rad51 recombinase, which acts downstream of the MRX complex in double-strand break (DSB) repair, regulates replicative senescence through a separate pathway operating in opposition to the MRX-Tel1-Rif2 pathway. Moreover, defects in several additional proteins implicated in DSB repair (Rif1 and Sae2) confer only transient effects during early or late stages of replicative senescence, respectively...

Upregulation of miR-760 and miR-186 Is Associated with Replicative Senescence in Human Lung Fibroblast Cells

Lee, Young-Hoon; Kim, Soo Young; Bae, Young-Seuk
Fonte: Korean Society for Molecular and Cellular Biology Publicador: Korean Society for Molecular and Cellular Biology
Tipo: Artigo de Revista Científica
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We have previously shown that microRNAs (miRNAs) miR-760, miR-186, miR-337-3p, and miR-216b stimulate premature senescence through protein kinase CK2 (CK2) down-regulation in human colon cancer cells. Here, we examined whether these four miRNAs are involved in the replicative senescence of human lung fibroblast IMR-90 cells. miR-760 and miR-186 were significantly upregulated in replicatively senescent IMR-90 cells, and their joint action with both miR-337-3p and miR-216b was necessary for efficient downregulation of the α subunit of CK2 (CK2α) in IMR-90 cells. A mutation in any of the four miRNA-binding sequences within the CK2α 3′-untranslated region (UTR) indicated that all four miRNAs should simultaneously bind to the target sites for CK2α downregulation. The four miRNAs increased senescence-associated β-galactosidase (SA-β-gal) staining, p53 and p21Cip1/WAF1 expression, and reactive oxygen species (ROS) production in proliferating IMR-90 cells. CK2α over-expression almost abolished this event. Taken together, the present results suggest that the upregulation of miR-760 and miR-186 is associated with replicative senescence in human lung fibroblast cells, and their cooperative action with miR-337-3p and miR-216b may induce replicative senescence through CK2α downregulation-dependent ROS generation.

Genome-Wide Loss-of-Function Genetic Screens Identify Novel Senescence Genes and Putative Tumor Suppressors

Burrows, Anna
Fonte: Harvard University Publicador: Harvard University
Tipo: Thesis or Dissertation
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During every cell cycle and upon exogenous stress, tumor suppression programs are engaged to ensure genomic stability. In response to replicative aging and oncogenic stimuli, the p53 and Rb pathways are activated to prevent the proliferation of damaged cells. Several lines of evidence suggest that escape from senescence is a crucial early step in oncogenic progression. A major challenge in the cancer field is to combine genomic information regarding cancer-associated genetic changes with high-throughput functional studies, in order to confirm genetic requirements and pinpoint biological roles of these perturbed genes in oncogenesis. Furthermore, a complete genetic understanding of replicative senescence, and how it might be bypassed, is lacking. We describe here two genome scale loss-of-function genetic screens that interrogate these tumor suppressor programs. We utilized a unique sensitization approach to isolate senescence pathways and unmask compensatory mechanisms that may have been difficult to identify in previous studies. These genetic screens have generated comprehensive and validated datasets of putative senescence and p53 pathway genes. We present this dataset as a high-quality resource for further investigation into these biological pathways. We have uncovered several genes in distinct biological pathways which have not been demonstrated to have a functional role in senescence...

Vieillissement vasculaire chez des patients athérosclérotiques: Sénescence prématurée des cellules endothéliales?

Voghel, Guillaume
Fonte: Université de Montréal Publicador: Université de Montréal
Tipo: Thèse ou Mémoire numérique / Electronic Thesis or Dissertation
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La dysfonction de l’endothélium vasculaire, associée à une diminution de ses propriétés vasorelaxantes et anti-thrombogéniques, survient avec le vieillissement mais également chez de plus jeunes patients athérosclérotiques présentant plusieurs facteurs de risque cardiovasculaire. Au niveau cellulaire, le vieillissement des cellules endothéliales (CE) mène à un état irréversible de non division cellulaire appelé sénescence. Ces cellules sénescentes présentent des changements spécifiques au niveau de leur morphologie et de l’expression génique, menant à leur dysfonction. La sénescence dite réplicative est déclenchée par le raccourcissement des télomères survenant à chaque division cellulaire, mais peut également être induite prématurément par le stress oxydant (SIPS). L’objectif principal de cette étude est de caractériser la sénescence de CE vasculaires isolées à partir de patients athérosclérotiques, et d’observer l’impact des facteurs de risque sur cette sénescence. Afin de confirmer la contribution des deux principales voies de la sénescence, nous avons par la suite étudié conjointement ou séparément, l’impact d’un traitement chronique avec un antioxydant sur la sénescence de CE...

Senescence-associated β-galactosidase activity in the in vitro ovarian stromal fibroblasts; Actividad β-galactosidasa asociada con la senescencia en fibroblastos del estroma ovárico in vitro; Atividade β-galactosidase associada com a senescência em fibroblastos do estroma ovariano in vitro

Chuaire-Noack, Lilian; García-Morcote, Cristian; Ramírez-Clavijo, Sandra Rocío
Fonte: Universidade do Rosário Publicador: Universidade do Rosário
Tipo: Artigo de Revista Científica Formato: application/pdf
Publicado em 27/05/2011 Português
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Introduction: A growing biological research field is the cellular senescence, a mechanism that has been associated, under certain circumstances, with malignant transformation. Given the high incidence of ovarian cancer and its main origin from the ovarian surface epithelium, as well as the possibility that an epithelial-mesenchymal transition occurs, we evaluated both the in vitro growth of stromal fibroblasts from the ovarian cortex and their β-galactosidase activity at pH 6, enzyme whose expression is considered as a marker of replicative senescence. Methods: 48 samples of ovarian cortical fibroblasts from donors without a history of cancer were serially cultured until the end of their replicative life. β-galactosidase activity at pH 6 was quantified in each passage by the chemiluminiscent method. As control, we used ovarian epithelial cell cultures from the same donors. The enzyme activity was also evaluated in fibroblasts previously induced to senescence by exposure to hydrogen peroxide. Results: The analysis of the enzyme activity and the replicative capacity taken together showed that the fibroblast cultures reached the senescent state at passages 4-5, as what happened with the control epithelial cells. Fibroblasts induced to senescence showed high variability in the values of enzymatic activity. Conclusions: The similarity between both types of cells in reaching the senescent state deserves to be taken into account in relation to the epithelialmesenchymal transition that has been proposed to explain their behavior in the genesis of cancer arising from ovarian surface epithelium. Low β-galactosidase activity values at pH 6 would suggest possible inactivation of the response pathways to oxidative stress.; Introducción: Un campo de investigación creciente de la biología es la senescencia celular...

Participación de p19INK4d en la inducción de senescencia genotóxica y replicativa; Role of p19INK4d in the induction of genotoxic-induced and replicative senescence

Sonzogni, Silvina Verónica
Fonte: Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires Publicador: Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires
Tipo: info:eu-repo/semantics/doctoralThesis; tesis doctoral; info:eu-repo/semantics/publishedVersion Formato: application/pdf
Publicado em //2012 Português
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A lo largo de la evolución, los organismos con tejidos renovables han desarrollado mecanismos para prevenir la tumorigénesis. Entre ellos, podemos mencionar a la senescencia celular y a la apoptosis. La senescencia se caracteriza por el arresto permanente del ciclo celular en respuesta a insultos tanto endógenos como exógenos. En los últimos años se han estudiando las moléculas involucradas en la activación de este mecanismo, destacándose la participación de los inhibidores de quinasas dependientes de ciclinas (CKIs) p21Cip1, p16INK4a y p15INK4b. En nuestro laboratorio se ha demostrado que la proteína p19INK4d (p19), un miembro de la familia INK4 de CKIs, se induce significativamente en respuesta a diversos genotóxicos aumentando la eficiencia de la reparación del ADN. El daño al ADN es un agente causal común de la respuesta senescente, independientemente del estímulo que le da origen. Los efectos provocados por diferentes inductores, tales como las especies reactivas de oxigeno (considerablemente aumentadas a lo largo del envejecimiento), los agentes genotóxicos (frecuentemente empleados en quimioterapia) o la activación de oncogenes, culminan dañando al ADN y activando en consecuencia mecanismos de arresto del ciclo celular. El arresto es dependiente de factores que controlan la progresión del ciclo tales como p53 y pRb-p16. Si bien estos son lo principales efectores moleculares involucrados en la iniciación y mantenimiento del estado de senescencia...