Página 14 dos resultados de 2140 itens digitais encontrados em 0.009 segundos

Gamma-tocotrienol modulation of senescence-associated gene expression prevents cellular aging in human diploid fibroblasts

Makpol,Suzana; Zainuddin,Azalina; Chua,Kien Hui; Yusof,Yasmin Anum Mohd; Ngah,Wan Zurinah Wan
Fonte: Faculdade de Medicina / USP Publicador: Faculdade de Medicina / USP
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2012 Português
Relevância na Pesquisa
37.84495%
OBJECTIVE: Human diploid fibroblasts undergo a limited number of cellular divisions in culture and progressively reach a state of irreversible growth arrest, a process termed cellular aging. The beneficial effects of vitamin E in aging have been established, but studies to determine the mechanisms of these effects are ongoing. This study determined the molecular mechanism of γ-tocotrienol, a vitamin E homolog, in the prevention of cellular aging in human diploid fibroblasts using the expression of senescence-associated genes. METHODS: Primary cultures of young, pre-senescent, and senescent fibroblast cells were incubated with γ-tocotrienol for 24 h. The expression levels of ELN, COL1A1, MMP1, CCND1, RB1, and IL6 genes were determined using the quantitative real-time polymerase chain reaction. Cell cycle profiles were determined using a FACSCalibur Flow Cytometer. RESULTS: The cell cycle was arrested in the G0/G1 phase, and the percentage of cells in S phase decreased with senescence. CCND1, RB1, MMP1, and IL6 were upregulated in senescent fibroblasts. A similar upregulation was not observed in young cells. Incubation with γ-tocotrienol decreased CCND1 and RB1 expression in senescent fibroblasts, decreased cell populations in the G0/G1 phase and increased cell populations in the G2/M phase. γ-Tocotrienol treatment also upregulated ELN and COL1A1 and downregulated MMP1 and IL6 expression in young and senescent fibroblasts. CONCLUSION: γ-Tocotrienol prevented cellular aging in human diploid fibroblasts...

The cellular level of telomere dysfunction determines induction of senescence or apoptosis in vivo

Lechel, André; Satyanarayana, Ande; Ju, Zhenyu; Plentz, Ruben R; Schaetzlein, Sonja; Rudolph, Cornelia; Wilkens, Ludwig; Wiemann, Stephanie U; Saretzki, Gabriele; Malek, Nisar P; Manns, Michael P; Buer, Jan; Rudolph, K Lenhard
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
37.890496%
Telomere dysfunction induces two types of cellular response: cellular senescence and apoptosis. We analysed the extent to which the cellular level of telomere dysfunction and p53 gene status affect these cellular responses in mouse liver using the experimental system of TRF2 inhibition by a dominant-negative version of the protein (TRF2ΔBΔM). We show that the level of telomere dysfunction correlates with the level of TRF2ΔBΔM protein expression resulting in chromosomal fusions, aberrant mitotic figures and aneuploidy of liver cells. These alterations provoked p53-independent apoptosis, but a strictly p53-dependent senescence response in distinct populations of mouse liver cells depending on the cellular level of TRF2ΔBΔM expression. Apoptosis was associated with higher expression of TRF2ΔBΔM, whereas cellular senescence was associated with low levels of TRF2ΔBΔM expression. Our data provide experimental evidence that induction of senescence or apoptosis in vivo depends on the cellular level of telomere dysfunction and differentially on p53 gene function.

Regulation of ploidy and senescence by the AMPK-related kinase NUAK1

Humbert, Nicolas; Navaratnam, Naveenan; Augert, Arnaud; Da Costa, Marco; Martien, Sébastien; Wang, Jing; Martinez, Dolores; Abbadie, Corinne; Carling, David; de Launoit, Yvan; Gil, Jesus; Bernard, David
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
37.869585%
Senescence is an irreversible cell-cycle arrest that is elicited by a wide range of factors, including replicative exhaustion. Emerging evidences suggest that cellular senescence contributes to ageing and acts as a tumour suppressor mechanism. To identify novel genes regulating senescence, we performed a loss-of-function screen on normal human diploid fibroblasts. We show that downregulation of the AMPK-related protein kinase 5 (ARK5 or NUAK1) results in extension of the cellular replicative lifespan. Interestingly, the levels of NUAK1 are upregulated during senescence whereas its ectopic expression triggers a premature senescence. Cells that constitutively express NUAK1 suffer gross aneuploidies and show diminished expression of the genomic stability regulator LATS1, whereas depletion of NUAK1 with shRNA exerts opposite effects. Interestingly, a dominant-negative form of LATS1 phenocopies NUAK1 effects. Moreover, we show that NUAK1 phosphorylates LATS1 at S464 and this has a role in controlling its stability. In summary, our work highlights a novel role for NUAK1 in the control of cellular senescence and cellular ploidy.

A High-Throughput Method to Identify Novel Senescence-Inducing Compounds

Ewald, Jonathan A.; Peters, Noel; Desotelle, Joshua A.; Hoffmann, F. Michael; Jarrard, David F.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
37.86447%
Cellular senescence is a persistently growth-arrested phenotype in normal and transformed cells induced by non-cytotoxic stress. Cytostasis as a method of cancer treatment has recently generated significant interest. Research into the induction of cellular senescence as cancer therapy has been hindered by a lack of compounds that efficiently induce this response. We describe a semiautomated high-throughput method to identify library compounds that induce senescence using prostate cancer cells cultured in 96 well plates. Primary hits are identified by low cell numbers after 3 days in culture, measured by Hoechst 33342 fluorescence. A secondary visual assessment of senescence-associated β-galactosidase staining and cellular morphology in the same wells distinguishes senescence from quiescence, apoptosis and other false-positives. This method was used to screen a 4160 compound library of known bioactive compounds and natural products at a 10μM dose. Candidate compounds were further selected based on persistent growth arrest after drug removal and increased expression of previously described senescence marker genes. Four lead compounds not previously associated with senescence were identified for further investigation. This is the first successful assay to identify novel agents from compound libraries based on senescence-induction in cancer cells.

EGFR and mutant p53 expand esophageal cellular subpopulation capable of epithelial-to-mesenchymal transition through ZEB transcription factors

Ohashi, Shinya; Natsuizaka, Mitsuteru; Wong, Gabrielle S.; Michaylira, Carmen Z.; Grugan, Katharine D.; Stairs, Douglas B.; Kalabis, Jiri; Vega, Maria E.; Kalman, Ross A.; Nakagawa, Momo; Klein-Szanto, Andres J; Herlyn, Meenhard; Diehl, J. Alan; Rustgi, A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
37.871072%
Transforming growth factor (TGF)-β is a potent inducer of epithelial to mesenchymal transition (EMT). However, it remains elusive as to which molecular mechanisms determine the cellular capacity to undergo EMT in response to TGF-β. We have found that both epidermal growth factor receptor (EGFR) overexpression and mutant p53 tumor suppressor genes contribute to enrichment of an EMT-competent cellular subpopulation amongst telomerase-immortalized human esophageal epithelial cells during malignant transformation. EGFR overexpression triggers oncogene-induced senescence, accompanied by induction of cyclin dependent kinase inhibitors p15INK4B, p16INK4A and p21. Interestingly, a subpopulation of cells emerges by negating senescence without loss of EGFR overexpression. Such cell populations express increased levels of zinc finger E-box binding (ZEB) transcription factors ZEB1 and ZEB2, and undergo EMT upon TGF-β stimulation. Enrichment of EMT-competent cells was more evident in the presence of p53 mutation, which diminished EGFR-induced senescence. RNA interference directed against ZEB resulted in induction of p15INK4B and p16INK4A, reactivating the EGFR-dependent senescence program. Importantly, TGF-β-mediated EMT did not take place when cellular senescence programs were activated by either ZEB knockdown or activation of wild-type p53 function. Thus...

The Splicing Factor SRSF1 as a Marker for Endothelial Senescence

Blanco, Francisco Javier; Bernabéu, Carmelo
Fonte: Frontiers Research Foundation Publicador: Frontiers Research Foundation
Tipo: Artigo de Revista Científica
Publicado em 28/03/2012 Português
Relevância na Pesquisa
37.86447%
Aging is the major risk factor per se for the development of cardiovascular diseases. The senescence of the endothelial cells (ECs) that line the lumen of blood vessels is the cellular basis for these age-dependent vascular pathologies, including atherosclerosis and hypertension. During their lifespan, ECs may reach a stage of senescence by two different pathways; a replicative one derived from their preprogrammed finite number of cell divisions; and one induced by stress stimuli. Also, certain physiological stimuli, such as transforming growth factor-β, are able to modulate cellular senescence. Currently, the cellular aging process is being widely studied to identify novel molecular markers whose changes correlate with senescence. This review focuses on the regulation of alternative splicing mediated by the serine–arginine splicing factor 1 (SRSF1, or ASF/SF2) during endothelial senescence, a process that is associated with a differential subcellular localization of SRSF1, which typically exhibits a scattered distribution throughout the cytoplasm. Based on its senescence-dependent involvement in alternative splicing, we postulate that SRSF1 is a key marker of EC senescence, regulating the expression of alternative isoforms of target genes such as endoglin (ENG)...

SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice

Yao, Hongwei; Chung, Sangwoon; Hwang, Jae-woong; Rajendrasozhan, Saravanan; Sundar, Isaac K.; Dean, David A.; McBurney, Michael W.; Guarente, Leonard; Gu, Wei; RÖnty, Mikko; Kinnula, Vuokko L.; Rahman, Irfan
Fonte: American Society for Clinical Investigation Publicador: American Society for Clinical Investigation
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
37.871072%
Chronic obstructive pulmonary disease/emphysema (COPD/emphysema) is characterized by chronic inflammation and premature lung aging. Anti-aging sirtuin 1 (SIRT1), a NAD+-dependent protein/histone deacetylase, is reduced in lungs of patients with COPD. However, the molecular signals underlying the premature aging in lungs, and whether SIRT1 protects against cellular senescence and various pathophysiological alterations in emphysema, remain unknown. Here, we showed increased cellular senescence in lungs of COPD patients. SIRT1 activation by both genetic overexpression and a selective pharmacological activator, SRT1720, attenuated stress-induced premature cellular senescence and protected against emphysema induced by cigarette smoke and elastase in mice. Ablation of Sirt1 in airway epithelium, but not in myeloid cells, aggravated airspace enlargement, impaired lung function, and reduced exercise tolerance. These effects were due to the ability of SIRT1 to deacetylate the FOXO3 transcription factor, since Foxo3 deficiency diminished the protective effect of SRT1720 on cellular senescence and emphysematous changes. Inhibition of lung inflammation by an NF-κB/IKK2 inhibitor did not have any beneficial effect on emphysema. Thus, SIRT1 protects against emphysema through FOXO3-mediated reduction of cellular senescence...

Suppressed Expression of T-Box Transcription Factors Is Involved in Senescence in Chronic Obstructive Pulmonary Disease

Acquaah-Mensah, George K.; Malhotra, Deepti; Vulimiri, Madhulika; McDermott, Jason E.; Biswal, Shyam
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
37.83597%
Chronic obstructive pulmonary disease (COPD) is a major global health problem. The etiology of COPD has been associated with apoptosis, oxidative stress, and inflammation. However, understanding of the molecular interactions that modulate COPD pathogenesis remains only partly resolved. We conducted an exploratory study on COPD etiology to identify the key molecular participants. We used information-theoretic algorithms including Context Likelihood of Relatedness (CLR), Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNE), and Inferelator. We captured direct functional associations among genes, given a compendium of gene expression profiles of human lung epithelial cells. A set of genes differentially expressed in COPD, as reported in a previous study were superposed with the resulting transcriptional regulatory networks. After factoring in the properties of the networks, an established COPD susceptibility locus and domain-domain interactions involving protein products of genes in the generated networks, several molecular candidates were predicted to be involved in the etiology of COPD. These include COL4A3, CFLAR, GULP1, PDCD1, CASP10, PAX3, BOK, HSPD1, PITX2, and PML. Furthermore, T-box (TBX) genes and cyclin-dependent kinase inhibitor 2A (CDKN2A)...

MicroRNA-152 and -181a participate in human dermal fibroblasts senescence acting on cell adhesion and remodeling of the extra-cellular matrix

Mancini, Mara; Saintigny, Gaelle; Mahé, Christian; Annicchiarico-Petruzzelli, Margherita; Melino, Gerry; Candi, Eleonora
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Publicado em 09/12/2012 Português
Relevância na Pesquisa
37.871072%
Ageing of human skin is associated with phenotypic changes in the cutaneous cells; the major functional markers of ageing occur as consequences of dermal and epidermal cell senescence and of structural and compositional remodeling of normally long-lived dermal extracellular matrix proteins. Understanding the contribution of the dermal cells in skin ageing is a key question, since this tissue is particularly important for skin integrity and its properties can affect the epidermis. Several microRNAs have been shown to be involved in the regulation of pathways involved in cellular senescence and exerted important effects on tissues ageing. In this study, we demonstrate that the expression of miR-152 and miR-181a increased during the human dermal fibroblasts senescence and that their overexpression, is sufficient to induce cellular senescence in early-passage cells. The increase of these miRNAs during cells senescence was accompanied by a decrease in integrin α and collagen XVI expression at mRNA and/or protein levels resulting in reduced cellular adhesion and suggesting extracellular matrix remodeling. These findings indicate that changes in miRNAs expression, by modulating the levels of adhesion proteins and extra-cellular matrix components...

Platelet-derived growth factor B induces senescence and transformation in normal human fibroblasts

Vindrieux, David; Gras, Baptiste; Garcia-Belinchon, Merce; Mourah, Samia; Lebbe, Céleste; Augert, Arnaud; Bernard, David
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Publicado em 15/07/2013 Português
Relevância na Pesquisa
37.86447%
Normal cells enter a senescent state upon aberrant oncogenic signals and this response inhibits tumor initiation and progression. It is now well admitted that intracellular and membrane localized oncogenes can illicit oncogene induced senescence. However, the effect of mitogenic growth factor on cellular senescence is so far largely unknown. Here we show that normal human dermal fibroblasts display a complex response to Platelet derived growth factor B (PDGFB) expression. Indeed, PDGFB expression induces, in the same cell population, both senescence and cellular transformation. Remarkably both populations are sustained with passages suggesting that transformed cells eventually enter a senescent state. This senescence state is p53 dependent as inhibiting the p53 pathway blocks the ability of PDGFB to induce senescence and results in strong cellular transformation increase upon PDGFB expression. The relevance of these observations is supported by the fact that human dermatofibrosarcoma protuberans, skin tumors arising from constitutive PDGFB production with little aggressiveness, also display some senescence hallmarks. Together these data support the view that PDGFB, a mitogenic growth factor, has a limited ability to induce senescence. We propose that this low level of senescence might decrease the transforming ability of this factor without totally abolishing it.

Friend or foe: emerging role of nuclear factor kappa-light-chain-enhancer of activated B cells in cell senescence

Mowla, Sophia N; Perkins, Neil D; Jat, Parmjit S
Fonte: Dove Medical Press Publicador: Dove Medical Press
Tipo: Artigo de Revista Científica
Publicado em 04/09/2013 Português
Relevância na Pesquisa
37.869585%
The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) proteins are a family of ubiquitously expressed transcription factors that regulate the response to cellular stress. They mediate innate and adaptive immunity through the initiation of an inflammatory response to pro-inflammatory signals. The role of persistent inflammation in aiding tumor development has led to the NF-κB family of transcription factors being strongly implicated in promoting cancer. However, recent studies have now revealed that NF-κB can also function as a tumor suppressor through the induction of cellular senescence. Cellular senescence is a stable cell cycle arrest that normal cells undergo in response to a variety of intrinsic and extrinsic stimuli including: progressive telomere shortening, changes in telomeric structure, or other forms of genotoxic stress. Senescence can compromise tissue repair and regeneration, contributing to tissue and organismal aging via the accumulation of senescent cells, depletion of stem/progenitor cells and secretion of an array of inflammatory cytokines, chemokines, and matrix metalloproteinases. Senescence can also lead to the removal of potentially cancerous cells, thereby acting as a potent tumor suppressor mechanism. Herein...

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
Português
Relevância na Pesquisa
37.83597%
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...

mRNA decay factor AUF1 maintains normal aging, telomere maintenance and suppression of senescence by activation of telomerase transcription

Pont, Adam R.; Sadri, Navid; Hsiao, Susan J.; Smith, Susan; Schneider, Robert J.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
37.871072%
Inflammation is associated with DNA damage, cellular senescence and aging. Cessation of the inflammatory cytokine response is mediated in part through cytokine mRNA degradation facilitated by RNA binding proteins, including AUF1. We report a major unrecognized function of AUF1 – it activates telomerase expression, suppresses cellular senescence and maintains normal aging. AUF1 deficient mice undergo striking telomere erosion, markedly increased DNA damage responses at telomere ends, pronounced cellular senescence and rapid premature aging that increases with successive generations, which can be rescued in AUF1 knockout mice and their cultured cells by resupplying AUF1 expression. AUF1 binds and strongly activates the transcription promoter for telomerase catalytic subunit Tert. In addition to directing inflammatory cytokine mRNA decay, AUF1 destabilizes cell cycle checkpoint mRNAs, preventing cellular senescence. Thus, a single gene, AUF1, links maintenance of telomere length and normal aging to attenuation of inflammatory cytokine expression and inhibition of cellular senescence.

KNDC1 knockdown protects human umbilical vein endothelial cells from senescence

ZHANG, CHUNYAN; ZHEN, YONG-ZHAN; LIN, YA-JUN; LIU, JIANG; WEI, JIE; XU, RONG; HU, GANG
Fonte: D.A. Spandidos Publicador: D.A. Spandidos
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
37.86447%
KNDC1 (kinase noncatalytic C-lobe domain containing 1), a brain-specific Ras guanine nucleotide exchange factor, controls the negative regulation of neuronal dendrite growth. However, the effect of KNDC1 on cellular senescence remains to be elucidated. The present study investigated the impact of KNDC1 knockdown on human endothelial cell senescence and the mechanisms underlying this effect. Human umbilical vein endothelial cells (HUVECs) cultured in vitro were used as a model of biological aging. Senescence-associated β-galactosidase staining was used to detect cellular senescence and flow cytometry was employed to determine cell cycle progression. Quantitative polymerase chain reaction (qPCR) and western blot analysis were utilized to investigate mRNA transcription and protein expression. In the HUVECs, a senescence-like phenotypes developed with increasing passage number in vitro, which were associated with a progressive increase in the transcription and expression of KNDC1. KNDC1 knockdown promoted cell proliferation and partially reversed cellular senescence and cell cycle arrest in the G0/G1 phase in aging HUVECs. Investigations into the mechanism underlying this effect demonstrated that KNDC1 knockdown promoted HUVEC proliferation via the extracellular signal-regulated kinase signaling pathway and delayed HUVEC senescence by inhibiting the p53-p21-p16 transduction cascade. In addition...

SIRT1 Suppresses the Senescence-Associated Secretory Phenotype through Epigenetic Gene Regulation

Hayakawa, Tomohisa; Iwai, Mika; Aoki, Satoshi; Takimoto, Koichi; Maruyama, Mitsuo; Maruyama, Wakako; Motoyama, Noboru
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 30/01/2015 Português
Relevância na Pesquisa
37.871072%
Senescent cells develop a pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). As many SASP components affect surrounding cells and alter their microenvironment, SASP may be a key phenomenon in linking cellular senesence with individual aging and age-related diseases. We herein demonstrated that the expression of Sirtuin1 (SIRT1) was decreased and the expression of SASP components was reciprocally increased during cellular senescence. The mRNAs and proteins of SASP components, such as IL-6 and IL-8, quickly accumulated in SIRT1-depleted cells, and the levels of these factors were also higher than those in control cells, indicating that SIRT1 negatively regulated the expression of SASP factors at the transcriptional level. SIRT1 bound to the promoter regions of IL-8 and IL-6, but dissociated from them during cellular senescence. The acetylation of Histone H3 (K9) and H4 (K16) of the IL-8 and IL-6 promoter regions gradually increased during cellular senescence. In SIRT1-depleted cells, the acetylation levels of these regions were already higher than those in control cells in the pre-senescent stage. Moreover, these acetylation levels in SIRT1-depleted cells were significantly higher than those in control cells during cellular senescence. These results suggest that SIRT1 repressed the expression of SASP factors through the deacetylation of histones in their promoter regions.

Nicotinamide Exerts Antioxidative Effects on Senescent Cells

Kwak, Ju Yeon; Ham, Hyun Joo; Kim, Cheol Min; Hwang, Eun Seong
Fonte: Korean Society for Molecular and Cellular Biology Publicador: Korean Society for Molecular and Cellular Biology
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
37.869585%
Nicotinamide (NAM) has been shown to suppress reactive oxygen species (ROS) production in primary human fibroblasts, thereby extending their replicative lifespan when added to the medium during long-term cultivation. Based on this finding, NAM is hypothesized to affect cellular senescence progression by keeping ROS accumulation low. In the current study, we asked whether NAM is indeed able to reduce ROS levels and senescence phenotypes in cells undergoing senescence progression and those already in senescence. We employed two different cellular models: MCF-7 cells undergoing senescence progression and human fibroblasts in a state of replicative senescence. In both models, NAM treatment substantially decreased ROS levels. In addition, NAM attenuated the expression of the assessed senescence phenotypes, excluding irreversible growth arrest. N-acetyl cysteine, a potent ROS scavenger, did not have comparable effects in the tested cell types. These data show that NAM has potent antioxidative as well as anti-senescent effects. Moreover, these findings suggest that NAM can reduce cellular deterioration caused by oxidative damage in postmitotic cells in vivo.

Zinc finger protein 637 protects cells against oxidative stress-induced premature senescence by mTERT-mediated telomerase activity and telomere maintenance

Gao, B; Li, K; Wei, Y-Y; Zhang, J; Li, J; Zhang, L; Gao, J-P; Li, Y-Y; Huang, L-G; Lin, P; Wei, Y-Q
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
37.88788%
Oxidative stress is believed to be an important inducer of cellular senescence and aging. Zinc finger protein 637 (Zfp637), which belongs to the Krüppel-like protein family, has been hypothesized to play a role in oxidative stress. Nevertheless, the precise function of Zfp637 has seldom been reported, and it remains unclear whether Zfp637 is involved in oxidative stress-induced premature senescence. In this study, we show that the endogenous expression levels of Zfp637 and mouse telomerase reverse transcriptase (mTERT) are downregulated during oxidative stress-induced premature senescence and in senescent tissues from naturally aged mice. The overexpression of Zfp637 markedly increases mTERT expression and telomerase activity, maintains telomere length, and inhibits both H2O2 and D-galactose-induced senescence accompanied by a reduction in the production of reactive oxygen species (ROS). In contrast, the knockdown of Zfp637 significantly aggravates cellular senescence by downregulating mTERT and telomerase activity, accelerating telomere shortening, and increasing ROS accumulation. In addition, the protective effect of Zfp637 against premature senescence is abrogated in the absence of mTERT. We further confirm that Zfp637 binds to and transactivates the mTERT promoter (−535/−502) specifically. As a result...

Gene expression profiling of replicative and induced senescence

Purcell, Maggie; Kruger, Adele; Tainsky, Michael A
Fonte: Taylor & Francis Publicador: Taylor & Francis
Tipo: Artigo de Revista Científica
Publicado em 31/10/2014 Português
Relevância na Pesquisa
37.867493%
Cellular senescence is a cell cycle arrest accompanied by high expression of cyclin dependent kinase inhibitors which counteract overactive growth signals, which serves as a tumor suppressive mechanism. Senescence can be a result of telomere shortening (natural or replicative senescence) or DNA damage resulting from exogenous stressors (induced senescence). Here, we performed gene expression profiling through RNA-seq of replicative senescence, adriamycin-induced senescence, H2O2-induced senescence, and 5-aza-2-deoxycytidine-induced senescence in order to profile the pathways controlling various types of senescence. Overall, the pathways common to all 4 types of senescence were related to inflammation and the innate immune system. It was also evident that 5-aza-induced senescence mirrors natural replicative senescence due to telomere shortening. We also examined the prevalence of senescence-associated secretory phenotype (SASP) factors in the RNA-seq data, showing that it is a common characteristic of all 4 types of senescence. In addition, we could discriminate changes in gene expression due to quiescence during cellular senescence from those that were specific to senescence.

Branched-Chain Amino Acids Enhance Premature Senescence through Mammalian Target of Rapamycin Complex I-Mediated Upregulation of p21 Protein

Nakano, Masayuki; Nakashima, Akio; Nagano, Taiki; Ishikawa, Shintaro; Kikkawa, Ushio; Kamada, Shinji
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 06/11/2013 Português
Relevância na Pesquisa
37.869585%
Branched-chain amino acids (BCAAs) have been applied as an oral supplementation to patients with liver cirrhosis. BCAAs not only improve nutritional status of patients but also decrease the incidence of liver cancer. Mammalian target of rapamycin (mTOR) links cellular metabolism with growth and proliferation in response to nutrients, energy, and growth factors. BCAAs, especially leucine, have been shown to regulate protein synthesis through mTOR activities. On the other hand, cellular senescence is suggested to function as tumor suppressor mechanisms, and induced by a variety of stimuli including DNA damage-inducing drugs. However, it is not clear how BCAA supplementation prevents the incidence of liver cancer in patients with cirrhosis. Here we showed that human cancer cells, HepG2 and U2OS, cultured in medium containing BCAAs with Fischer's ratio about 3, which was shown to have highest activities to synthesize and secrete of albumin, had higher activities to induce premature senescence and elevate mTORC1 activities. Furthermore, BCAAs themselves enhanced the execution of premature senescence induced by DNA damage-inducing drugs, which was effectively prevented by rapamycin. These results strongly suggested the contribution of the mTORC1 pathway to the regulation of premature senescence. Interestingly...

Gamma-tocotrienol modulation of senescence-associated gene expression prevents cellular aging in human diploid fibroblasts

Makpol, Suzana; Zainuddin, Azalina; Chua, Kien Hui; Yusof, Yasmin Anum Mohd; Ngah, Wan Zurinah Wan
Fonte: Universidade de São Paulo. Faculdade de Medicina Publicador: Universidade de São Paulo. Faculdade de Medicina
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; ; ; ; ; ; Formato: application/pdf
Publicado em 01/01/2012 Português
Relevância na Pesquisa
37.84495%
OBJECTIVE: Human diploid fibroblasts undergo a limited number of cellular divisions in culture and progressively reach a state of irreversible growth arrest, a process termed cellular aging. The beneficial effects of vitamin E in aging have been established, but studies to determine the mechanisms of these effects are ongoing. This study determined the molecular mechanism of γ-tocotrienol, a vitamin E homolog, in the prevention of cellular aging in human diploid fibroblasts using the expression of senescence-associated genes. METHODS: Primary cultures of young, pre-senescent, and senescent fibroblast cells were incubated with γ-tocotrienol for 24 h. The expression levels of ELN, COL1A1, MMP1, CCND1, RB1, and IL6 genes were determined using the quantitative real-time polymerase chain reaction. Cell cycle profiles were determined using a FACSCalibur Flow Cytometer. RESULTS: The cell cycle was arrested in the G0/G1 phase, and the percentage of cells in S phase decreased with senescence. CCND1, RB1, MMP1, and IL6 were upregulated in senescent fibroblasts. A similar upregulation was not observed in young cells. Incubation with γ-tocotrienol decreased CCND1 and RB1 expression in senescent fibroblasts, decreased cell populations in the G0/G1 phase and increased cell populations in the G2/M phase. γ-Tocotrienol treatment also upregulated ELN and COL1A1 and downregulated MMP1 and IL6 expression in young and senescent fibroblasts. CONCLUSION: γ-Tocotrienol prevented cellular aging in human diploid fibroblasts...