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Cellular Senescence Requires CDK5 Repression of Rac1 Activity

Alexander, Kamilah; Yang, Hai-Su; Hinds, Philip W.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /04/2004 Português
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Cellular senescence is a tumor-suppressive process characterized by an irreversible cell cycle exit, a unique morphology, and expression of senescence-associated β-galactosidase (SA-β-Gal). We report here a role for CDK5 in induction of senescent cytoskeletal changes. CDK5 activation is upregulated in senescing cells. The increased activity of CDK5 further reduces GTPase Rac1 activity and Pak activation. The repression of the activity of the GTPase Rac1 by CDK5 is required for expression of the senescent phenotype. CDK5 regulation of Rac1 activity is necessary for actin polymerization accompanying senescent morphology in response to expression of pRb, activated Ras, or continuous passage. Inhibition of CDK5 attenuates SA-β-Gal expression and blocks actin polymerization. These results point to a unique, nonneuronal role for CDK5 in regulation of Rac1 activity in senescence, illuminating the mechanisms underlying induction of senescence and the senescent shape change.

Loss of linker histone H1 in cellular senescence

Funayama, Ryo; Saito, Motoki; Tanobe, Hiroko; Ishikawa, Fuyuki
Fonte: The Rockefeller University Press Publicador: The Rockefeller University Press
Tipo: Artigo de Revista Científica
Publicado em 18/12/2006 Português
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Cellular senescence is a tumor-suppressing mechanism that is accompanied by characteristic chromatin condensation called senescence-associated heterochromatic foci (SAHFs). We found that individual SAHFs originate from individual chromosomes. SAHFs do not show alterations of posttranslational modifications of core histones that mark condensed chromatin in mitotic chromosomes, apoptotic chromatin, or transcriptionally inactive heterochromatin. Remarkably, SAHF-positive senescent cells lose linker histone H1 and exhibit increased levels of chromatin-bound high mobility group A2 (HMGA2). The expression of N-terminally enhanced green fluorescent protein (EGFP)–tagged histone H1 induces premature senescence phenotypes, including increased levels of phosphorylated p53, p21, and hypophosphorylated Rb, and a decrease in the chromatin-bound endogenous histone H1 level but not in p16 level accumulation or SAHF formation. However, the simultaneous ectopic expression of hemagglutinin-tagged HMGA2 and N-terminally EGFP-tagged histone H1 leads to significant SAHF formation (P < 0.001). It is known that histone H1 and HMG proteins compete for a common binding site, the linker DNA. These results suggest that SAHFs are a novel type of chromatin condensation involving alterations in linker DNA–binding proteins.

Magnesium deficiency accelerates cellular senescence in cultured human fibroblasts

Killilea, David W.; Ames, Bruce N.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Magnesium inadequacy affects more than half of the U.S. population and is associated with increased risk for many age-related diseases, yet the underlying mechanisms are unknown. Altered cellular physiology has been demonstrated after acute exposure to severe magnesium deficiency, but few reports have addressed the consequences of long-term exposure to moderate magnesium deficiency in human cells. Therefore, IMR-90 human fibroblasts were continuously cultured in magnesium-deficient conditions to determine the long-term effects on the cells. These fibroblasts did not demonstrate differences in cellular viability or plating efficiency but did exhibit a decreased replicative lifespan in populations cultured in magnesium-deficient compared with standard media conditions, both at ambient (20% O2) and physiological (5% O2) oxygen tension. The growth rates for immortalized IMR-90 fibroblasts were not affected under the same conditions. IMR-90 fibroblast populations cultured in magnesium-deficient conditions had increased senescence-associated β-galactosidase activity and increased p16INK4a and p21WAF1 protein expression compared with cultures from standard media conditions. Telomere attrition was also accelerated in cell populations from magnesium-deficient cultures. Thus...

Expression of H-RASV12 in a zebrafish model of Costello syndrome causes cellular senescence in adult proliferating cells

Santoriello, Cristina; Deflorian, Gianluca; Pezzimenti, Federica; Kawakami, Koichi; Lanfrancone, Luisa; d’Adda di Fagagna, Fabrizio; Mione, Marina
Fonte: The Company of Biologists Limited Publicador: The Company of Biologists Limited
Tipo: Artigo de Revista Científica
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Constitutively active, ‘oncogenic’ H-RAS can drive proliferation and transformation in human cancer, or be a potent inducer of cellular senescence. Moreover, aberrant activation of the Ras pathway owing to germline mutations can cause severe developmental disorders. In this study we have generated transgenic zebrafish that constitutively express low levels, or can be induced to express high levels, of oncogenic H-RAS. We observed that fish carrying the integrated transgene in their germline display several hallmarks of Costello syndrome, a rare genetic disease caused by activating mutations in the gene H-RAS, and can be used as a model for the disease. In Costello-like fish, low levels of oncogenic H-RAS expression are associated with both reduced proliferation and an increase in senescence markers in adult progenitor cell compartments in the brain and heart, together with activated DNA damage responses. Overexpression of H-RAS through a heat-shock-inducible promoter in larvae led to hyperproliferation, activation of the DNA damage response and tp53-dependent cell cycle arrest. Thus, oncogene-induced senescence of adult proliferating cells contributes to the development of Costello syndrome and provides an alternative pathway to transformation in the presence of widespread constitutively active H-RAS expression.

Biliverdin reductase A in the prevention of cellular senescence against oxidative stress

Kim, Sung Young; Kang, Hyun Tae; Choi, Hae Ri; Park, Sang Chul
Fonte: Korean Society for Biochemistry and Molecular Biology Publicador: Korean Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Biliverdin reductase A (BLVRA), an enzyme that converts biliverdin to bilirubin, has recently emerged as a key regulator of the cellular redox cycle. However, the role of BLVRA in the aging process remains unclear. To study the role of BLVRA in the aging process, we compared the stress responses of young and senescent human diploid fibroblasts (HDFs) to the reactive oxygen species (ROS) inducer, hydrogen peroxide (H2O2). H2O2 markedly induced BLVRA activity in young HDFs, but not in senescent HDFs. Additionally, depletion of BLVRA reduced the H2O2-dependent induction of heme oxygenase-1 (HO-1) in young HDFs, but not in senescent cells, suggesting an aging-dependent differential modulation of responses to oxidative stress. The role of BLVRA in the regulation of cellular senescence was confirmed when lentiviral RNAitransfected stable primary HDFs with reduced BLVRA expression showed upregulation of the CDK inhibitor family members p16, p53, and p21, followed by cell cycle arrest in G0-G1 phase with high expression of senescence-associated β-galactosidase. Taken together, these data support the notion that BLVRA contributes significantly to modulation of the aging process by adjusting the cellular oxidative status.

VentX trans-Activates p53 and p16ink4a to Regulate Cellular Senescence

Wu, Xiaoming; Gao, Hong; Ke, Weixiong; Hager, Martin; Xiao, Sheng; Freeman, Michael R.; Zhu, Zhenglun
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Cell senescence is a process of irreversible arrest of cell proliferation and plays an important role in tumor suppression. Recent studies showed that Wnt inhibition is a trigger of cellular senescence. Using methods of reverse genetics, we recently identified VentX, a human homolog of the vertebrate Xenopus Vent family of homeobox genes, as a novel Wnt repressor and a putative tumor suppressor in lymphocytic leukemia. Here, we show that VentX is a direct transcriptional activator of p53-p21 and p16ink4a-Rb tumor suppression pathways. Ectopic expression of VentX in cancer cells caused an irreversible cell cycle arrest with a typical senescence-like phenotype. Conversely, inhibition of VentX expression by RNA interference ameliorated chemotherapeutic agent-induced senescence in lymphocytic leukemia cells. The results of our study further reveal the mechanisms underlying tumor suppression function of VentX and suggest a role of VentX as a potential target in cancer prevention and treatment.

Cellular senescence in the glaucomatous outflow pathway

Liton, Paloma B.; Challa, Pratap; Stinnett, Sandra; Luna, Coralia; Epstein, David L.; Gonzalez, Pedro
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em //2005 Português
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The mechanisms responsible for the progressive malfunction of the trabecular meshwork (TM)–Schlemm’s canal (SC) conventional outflow pathway tissue in primary open angle glaucoma (POAG) are still not fully understood. To determine whether POAG is characterized by an accumulation of senescent cells, similar to what has been described in other diseases, we have compared the levels of the senescence marker senescence-associated-β-galactosidase (SA-β-gal) in the outflow pathway cells of POAG and age-matched control donors. POAG donors demonstrated a statistically significant fourfold increase in the percentage of SA-β-gal positive cells. These results suggest a potential role for cellular senescence in the pathophysiology of the outflow pathway.

Nuclear protein accumulation in cellular senescence and organismal aging revealed with a novel single-cell resolution fluorescence microscopy assay

De Cecco, Marco; Jeyapalan, Jessie; Zhao, Xiaoai; Tamamori-Adachi, Mimi; Sedivy, John M.
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Publicado em 16/10/2011 Português
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Replicative cellular senescence was discovered some 50 years ago. The phenotypes of senescent cells have been investigated extensively in cell culture, and found to affect essentially all aspects of cellular physiology. The relevance of cellular senescence in the context of age-associated pathologies as well as normal aging is a topic of active and ongoing interest. Considerable effort has been devoted to biomarker discovery to enable the microscopic detection of single senescent cells in tissues. One characteristic of senescent cells documented very early in cell culture studies was an increase in cell size and total protein content, but whether this occurs in vivo is not known. A limiting factor for studies of protein content and localization has been the lack of suitable fluorescence microscopy tools. We have developed an easy and flexible method, based on the merocyanine dye known as NanoOrange, to visualize and quantitatively measure total protein levels by high resolution fluorescence microscopy. NanoOrange staining can be combined with antibody-based immunofluorescence, thus providing both specific target and total protein information in the same specimen. These methods are optimally combined with automated image analysis platforms for high throughput analysis. We document here increasing protein content and density in nuclei of senescent human and mouse fibroblasts in vitro...

Interferon-β Induces Cellular Senescence in Cutaneous Human Papilloma Virus-Transformed Human Keratinocytes by Affecting p53 Transactivating Activity

Chiantore, Maria V.; Vannucchi, Serena; Accardi, Rosita; Tommasino, Massimo; Percario, Zulema A.; Vaccari, Gabriele; Affabris, Elisabetta; Fiorucci, Gianna; Romeo, Giovanna
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 16/05/2012 Português
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Interferon (IFN)-β inhibits cell proliferation and affects cell cycle in keratinocytes transformed by both mucosal high risk Human Papilloma Virus (HPV) and cutaneous HPV E6 and E7 proteins. In particular, upon longer IFN-β treatments, cutaneous HPV38 expressing cells undergo senescence. IFN-β appears to induce senescence by upregulating the expression of the tumor suppressor PML, a well known IFN-induced gene. Indeed, experiments in gene silencing via specific siRNAs have shown that PML is essential in the execution of the senescence programme and that both p53 and p21 pathways are involved. IFN-β treatment leads to a modulation of p53 phosphorylation and acetylation status and a reduction in the expression of the p53 dominant negative ΔNp73. These effects allow the recovery of p53 transactivating activity of target genes involved in the control of cell proliferation. Taken together, these studies suggest that signaling through the IFN pathway might play an important role in cellular senescence. This additional understanding of IFN antitumor action and mechanisms influencing tumor responsiveness or resistance appears useful in aiding further promising development of biomolecular strategies in the IFN therapy of cancer.

Deregulated telomere transcription causes replication-dependent telomere shortening and promotes cellular senescence

Maicher, André; Kastner, Lisa; Dees, Martina; Luke, Brian
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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Telomeres are transcribed into non-coding TElomeric Repeat containing RNAs (TERRA). We have employed a transcriptionally inducible telomere to investigate how telomere transcription affects telomere function in Saccharomyces cerevisiae. We report that telomere shortening resulting from high levels of telomere transcription stems from a DNA replication-dependent loss of telomere tracts, which can occur independent of both telomerase inhibition and homologous recombination. We show that in order for telomere loss to occur, transcription must pass through the telomere tract itself producing a TERRA molecule. We demonstrate that increased telomere transcription of a single telomere leads to a premature cellular senescence in the absence of a telomere maintenance mechanism (telomerase and homology directed repair). Similar rapid senescence and telomere shortening are also seen in sir2Δ cells with compromised telomere maintenance, where TERRA levels are increased at natural telomeres. These data suggest that telomere transcription must be tightly controlled to prevent telomere loss and early onset senescence.

Cellular Senescence Limits Regenerative Capacity and Allograft Survival

Braun, Heidi; Schmidt, Bernhard M.W.; Raiss, Mirja; Baisantry, Arpita; Mircea-Constantin, Dan; Wang, Shijun; Gross, Marie-Luise; Serrano, Manuel; Schmitt, Roland; Melk, Anette
Fonte: American Society of Nephrology Publicador: American Society of Nephrology
Tipo: Artigo de Revista Científica
Publicado em /09/2012 Português
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Long-term graft survival after kidney transplantation remains unsatisfactory and unpredictable. Interstitial fibrosis and tubular atrophy are major contributors to late graft loss; features of tubular cell senescence, such as increased p16INK4a expression, associate with these tubulointerstitial changes, but it is unknown whether the relationship is causal. Here, loss of the INK4a locus in mice, which allows escape from p16INK4a-dependent senescence, significantly reduced interstitial fibrosis and tubular atrophy and associated with improved renal function, conservation of nephron mass, and transplant survival. Compared with wild-type controls, kidneys from INK4a−/− mice developed significantly less interstitial fibrosis and tubular atrophy after ischemia-reperfusion injury. Consistently, mice that received kidney transplants from INK4a/ARF−/− donors had significantly better survival 21 days after life-supporting kidney transplantation and developed less tubulointerstitial changes. This correlated with higher proliferative rates of tubular cells and significantly fewer senescent cells. Taken together, these data suggest a pathogenic role of renal cellular senescence in the development of interstitial fibrosis and tubular atrophy and kidney graft deterioration by preventing the recovery from injury. Inhibiting premature senescence could have therapeutic benefit in kidney transplantation but has to be balanced against the risks of suspending antitumor defenses.

Centrosome Aberrations Associated with Cellular Senescence and p53 Localization at Supernumerary Centrosomes

Ohshima, Susumu
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
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Centrosome overduplication or amplification has been observed in many human cancers and in premalignant tissue, but the mechanisms leading to such centrosome aberrations are not fully understood. We previously showed that abnormal mitotic cells with supernumerary centrosomes increase with replicative senescence in human fibroblasts, especially in a polyploid subpopulation. This study examines localization of p53 protein at centrosomes in mitotic cells, which is often observed in association with DNA damage response, to investigate a possible association between p53 localization and numerical centrosome aberrations induced by cellular senescence. Cultures at later passages or the 4th day after exposure to H2O2 showed increased frequencies of mitotic cells with supernumerary centrosomes, especially in a polyploid subpopulation. Immunohistochemical analysis frequently showed p53-positive foci in mitotic cells, and some were localized at centrosomes. The number of p53-positive foci in mitotic cells and its localization to centrosomes increased with replicative and premature senescence. Supernumerary centrosomes showed higher frequencies of p53 localization compared to normally duplicated centrosomes. Centrosome-associated p53 protein was phosphorylated at Ser15. These data suggest a possible association between localization of p53 protein and numerical centrosome aberrations in replicatively or prematurely senescent cells.

Cilostazol induces cellular senescence and confers resistance to etoposide-induced apoptosis in articular chondrocytes

KIM, KANG MI; KIM, JONG MIN; YOO, YOUNG HYUN; KIM, JEUNG IL; PARK, YOUNG CHUL
Fonte: D.A. Spandidos Publicador: D.A. Spandidos
Tipo: Artigo de Revista Científica
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We recently reported that cilostazol protects chondrocytes against stress-induced apoptosis and prevents cartilage destruction in an osteoarthritis (OA) model. In the present study, we elucidate the mechanism underlying the protective effect induced by cilostazol against stress-induced apoptosis in chondrocytes. Cilostazol significantly reduced the expression of type II collagen and stimulated the accumulation of β-catenin in primary rat articular chondrocytes. Moreover, cilostazol-induced chondrocytes showed induction of senescent phenotypes, such as changes in cell morphology, decrease in cell proliferation and increase in specific senescence-associated β-galactosidase (SA-β-gal) staining. Moreover, dedifferentiated chondrocytes obtained by serial subculture showed cellular senescence that increased with passage number. In addition, the percentage of terminal dUTP nick end-labeling (TUNEL)-positive cells was higher when chondrocytes were treated with cilostazol and the apoptosis inducer etoposide than when the cells were treated with etoposide alone. Our findings suggest that cilostazol induces dedifferentiation and senescence in rat articular chondrocytes and renders them resistant to etoposide-induced apoptosis.

Autophagy and Cellular Senescence Mediated by Sox2 Suppress Malignancy of Cancer Cells

Cho, Yong-Yeon; Kim, Dong Joon; Lee, Hye Suk; Jeong, Chul-Ho; Cho, Eun-Jin; Kim, Myong-Ok; Byun, Sanguine; Lee, Kun-Yeong; Yao, Ke; Carper, Andria; Langfald, Alyssa; Bode, Ann M.; Dong, Zigang
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 25/02/2013 Português
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Autophagy is a critical cellular process required for maintaining cellular homeostasis in health and disease states, but the molecular mechanisms and impact of autophagy on cancer is not fully understood. Here, we found that Sox2, a key transcription factor in the regulation of the “stemness” of embryonic stem cells and induced-pluripotent stem cells, strongly induced autophagic phenomena, including intracellular vacuole formation and lysosomal activation in colon cancer cells. The activation occurred through Sox2-mediated ATG10 gene expression and resulted in the inhibition of cell proliferation and anchorage-independent colony growth ex vivo and tumor growth in vivo. Further, we found that Sox2-induced-autophagy enhanced cellular senescence by up-regulating tumor suppressors or senescence factors, including p16INK4a, p21 and phosphorylated p53 (Ser15). Notably, knockdown of ATG10 in Sox2-expressing colon cancer cells restored cancer cell properties. Taken together, our results demonstrated that regulation of autophagy mediated by Sox2 is a mechanism-driven novel strategy to treat human colon cancers.

Oncogene Induced Cellular Senescence Elicits an Anti-Warburg Effect

Li, Mingxi; Durbin, Kenneth R.; Sweet, Steve M. M.; Tipton, Jeremiah D.; Zheng, Yupeng; Kelleher, Neil L.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Cellular senescence, an irreversible cell cycle arrest induced by a diversity of stimuli, has been considered as an innate tumor suppressing mechanism with implications and applications in cancer therapy. Using a targeted proteomics approach we show that fibroblasts induced into senescence by expression of oncogenic Ras exhibit a decrease of global acetylation on all core histones, consistent with formation of senescence-associated heterochromatic foci. We also detected clear increases in repressive markers (e.g., >50% elevation of H3K27me2/3) along with decreases in histone marks associated with increased transcriptional expression/elongation (e.g., H3K36me2/3). Despite the increases in repressive marks of chromatin, 179 loci (of 2206 total) were found to be upregulated by global quantitative proteomics. The changes in the cytosolic proteome indicated an upregulation of mitochondrial proteins and downregulation of proteins involved in glycolysis. These alterations in primary metabolism are opposite of the well-known Warburg effect observed in cancer cells. This study significantly improves our understanding of stress-induced senescence and provides a potential application for triggering it in anti-proliferative strategies that target the primary metabolism in cancer cells.

From Cirrhosis to Hepatocellular Carcinoma: New Molecular Insights on Inflammation and Cellular Senescence

Ramakrishna, Gayatri; Rastogi, Archana; Trehanpati, Nirupama; Sen, Bijoya; Khosla, Ritu; Sarin, Shiv K.
Fonte: S. Karger AG Publicador: S. Karger AG
Tipo: Artigo de Revista Científica
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Sequential progression from chronic liver disease to fibrosis and to cirrhosis culminates in neoplasia in hepatocellular carcinoma (HCC). The preneoplastic setting of the cirrhotic background provides a conducive environment for cellular transformation. The role of classical inflammation in cirrhosis is widely known, but the exact mechanism linking inflammation and cancer remains elusive. Recent studies have elucidated roles for NF-κB, STAT3 and JNK as possible missing links. In addition, the “inflammasome” (a multiprotein complex and sensor of cellular damage) is a recently identified player in this field. The hallmarks of cirrhosis include necroinflammation, deposition of extracellular matrix and shortening of telomeres, leading to senescence and regeneration. Additionally, the accumulation of genetic/epigenetic changes propels atypical cells toward a malignant phenotype. This review provides recent information on the classical inflammatory pathway, together with a spotlight on inflammasomes and the immunomodulatory role of cellular senescence during the progression from cirrhosis to HCC. Moreover, lacunae in the current knowledge were identified and key questions raised on whether the observed adaptive responses are beneficial or detrimental to tissue homeostasis in a complex organ like liver.

Mitochondrial dysfunction induced by frataxin deficiency is associated with cellular senescence and abnormal calcium metabolism

Bolinches-Amorós, Arantxa; Mollá, Belén; Pla-Martín, David; Palau, Francesc; González-Cabo, Pilar
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Publicado em 13/05/2014 Português
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Friedreich ataxia is considered a neurodegenerative disorder involving both the peripheral and central nervous systems. Dorsal root ganglia (DRG) are the major target tissue structures. This neuropathy is caused by mutations in the FXN gene that encodes frataxin. Here, we investigated the mitochondrial and cell consequences of frataxin depletion in a cellular model based on frataxin silencing in SH-SY5Y human neuroblastoma cells, a cell line that has been used widely as in vitro models for studies on neurological diseases. We showed that the reduction of frataxin induced mitochondrial dysfunction due to a bioenergetic deficit and abnormal Ca2+ homeostasis in the mitochondria that were associated with oxidative and endoplasmic reticulum stresses. The depletion of frataxin did not cause cell death but increased autophagy, which may have a cytoprotective effect against cellular insults such as oxidative stress. Frataxin silencing provoked slow cell growth associated with cellular senescence, as demonstrated by increased SA-βgal activity and cell cycle arrest at the G1 phase. We postulate that cellular senescence might be related to a hypoplastic defect in the DRG during neurodevelopment, as suggested by necropsy studies.

Methamphetamine Accelerates Cellular Senescence through Stimulation of De Novo Ceramide Biosynthesis

Astarita, Giuseppe; Avanesian, Agnesa; Grimaldi, Benedetto; Realini, Natalia; Justinova, Zuzana; Panlilio, Leight V.; Basit, Abdul; Goldberg, Steven R.; Piomelli, Daniele
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 11/02/2015 Português
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Methamphetamine is a highly addictive psychostimulant that causes profound damage to the brain and other body organs. Post mortem studies of human tissues have linked the use of this drug to diseases associated with aging, such as coronary atherosclerosis and pulmonary fibrosis, but the molecular mechanism underlying these findings remains unknown. Here we used functional lipidomics and transcriptomics experiments to study abnormalities in lipid metabolism in select regions of the brain and, to a greater extent, peripheral organs and tissues of rats that self-administered methamphetamine. Experiments in various cellular models (primary mouse fibroblasts and myotubes) allowed us to investigate the molecular mechanisms of systemic inflammation and cellular aging related to methamphetamine abuse. We report now that methamphetamine accelerates cellular senescence and activates transcription of genes involved in cell-cycle control and inflammation by stimulating production of the sphingolipid messenger ceramide. This pathogenic cascade is triggered by reactive oxygen species, likely generated through methamphetamine metabolism via cytochrome P450, and involves the recruitment of nuclear factor-κB (NF-κB) to induce expression of enzymes in the de novo pathway of ceramide biosynthesis. Inhibitors of NF-κB signaling and ceramide formation prevent methamphetamine-induced senescence and systemic inflammation in rats self-administering the drug...

Modelling the onset of senescence at the G1/S cell cycle checkpoint

Mombach, José CM; Bugs, Cristhian A; Chaouiya, Claudine
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 27/10/2014 Português
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DNA damage (single or double-strand breaks) triggers adapted cellular responses. These responses are elicited through signalling pathways, which activate cell cycle checkpoints and basically lead to three cellular fates: cycle arrest promoting DNA repair, senescence (permanent arrest) or cell death. Cellular senescence is known for having a tumour-suppressive function and its regulation arouses a growing scientific interest. Here, we advance a qualitative model covering DNA damage response pathways, focusing on G1/S checkpoint enforcement, supposedly more sensitive to arrest than G2/M checkpoint.; Brazilian agency CNPq grants: (236673/2012-2, 304805/2012-2, 402547/2012-8), Instituto Gulbenkian de Ciência.

Étude du mécanisme de régulation de la sénescence et de p53 par la protéine SOCS1

Calabrese, Viviane
Fonte: Université de Montréal Publicador: Université de Montréal
Tipo: Thèse ou Mémoire numérique / Electronic Thesis or Dissertation
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Les mécanismes cellulaires anti-prolifératifs, lesquels comprennent l’apoptose, aussi appelée la mort cellulaire programmée, l’arrêt transitoire du cycle cellulaire et la sénescence, permettent à la cellule de prévenir, en réponse à différents stress, l’accumulation de mutations pouvant conduire à une prolifération incontrôlée et, éventuellement, au développement d’une tumeur. La régulation de ces différents mécanismes requiert l’activation de protéines appelées des suppresseurs de tumeur, dont le principal est p53. p53 est un facteur de transcription dont la stabilisation et l’activation conduit à une hausse de l’expression de gènes directement impliqués dans l’arrêt de la prolifération. Au cours des dernières années, l’ensemble des travaux sur p53 ont permis de mettre en évidence la complexité de sa fonction, de même que la multitude de voies de signalisation et de protéines avec lesquelles il coopère pour maintenir l’intégrité du génome. De ce fait, l’étude des mécanismes d’activation de p53 est de mise pour la compréhension de sa régulation et, éventuellement, pour la prévention et l’élaboration de nouvelles stratégies de traitement contre le cancer. L’objet de cette thèse est la mise en évidence d’un mécanisme d’activation de p53 et de la sénescence par la protéine SOCS1...