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Expression of Caveolin-1 Induces Premature Cellular Senescence in Primary Cultures of Murine Fibroblasts: Stress-Induced Premature Senescence Upregulates the Expression of Endogenous Caveolin-1

Volonte, Daniela; Zhang, Kun; Lisanti, Michael P.; Galbiati, Ferruccio
Fonte: The American Society for Cell Biology Publicador: The American Society for Cell Biology
Tipo: Artigo de Revista Científica
Publicado em /07/2002 Português
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Caveolae are vesicular invaginations of the plasma membrane. Caveolin-1 is the principal structural component of caveolae in vivo. Several lines of evidence are consistent with the idea that caveolin-1 functions as a “transformation suppressor” protein. In fact, caveolin-1 mRNA and protein expression are lost or reduced during cell transformation by activated oncogenes. Interestingly, the human caveolin-1 gene is localized to a suspected tumor suppressor locus (7q31.1). We have previously demonstrated that overexpression of caveolin-1 arrests mouse embryonic fibroblasts in the G0/G1 phase of the cell cycle through activation of a p53/p21-dependent pathway, indicating a role of caveolin-1 in mediating growth arrest. However, it remains unknown whether overexpression of caveolin-1 promotes cellular senescence in vivo. Here, we demonstrate that mouse embryonic fibroblasts transgenically overexpressing caveolin-1 show: 1) a reduced proliferative lifespan; 2) senescence-like cell morphology; and 3) a senescence-associated increase in β-galactosidase activity. These results indicate for the first time that the expression of caveolin-1 in vivo is sufficient to promote and maintain the senescent phenotype. Subcytotoxic oxidative stress is known to induce premature senescence in diploid fibroblasts. Interestingly...

Decreased Expression of Bmi1 Is Closely Associated with Cellular Senescence in Small Bile Ducts in Primary Biliary Cirrhosis

Sasaki, Motoko; Ikeda, Hiroko; Sato, Yasunori; Nakanuma, Yasuni
Fonte: American Society for Investigative Pathology Publicador: American Society for Investigative Pathology
Tipo: Artigo de Revista Científica
Publicado em /09/2006 Português
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Cellular senescence of biliary epithelial cells with p16INK4a and p21WAF1/Cip expression in damaged small bile ducts may be critical for progressive bile duct loss in primary biliary cirrhosis. We investigated the involvement of bmi1, a polycomb group gene repressing p16INK4a expression, in the pathogenesis of biliary cellular senescence. Bmi1 expression was examined immunohistochemically in livers taken from the patients with primary biliary cirrhosis (n = 18) and other diseased (n = 19) and normal livers (n = 16). We examined the effect of oxidative stress and a short interference RNA (siRNA) targeting bmi1 on cellular senescence in cultured mouse biliary epithelial cells. Bmi1 was widely expressed in the nuclei of biliary epithelial cells in the control livers. In contrast, bmi1 expression was significantly decreased in damaged small bile ducts in 43% of livers with primary biliary cirrhosis of stage 1/2, coordinating with the increased p16INK4a expression. In cultured biliary epithelial cells, oxidative stress by H2O2 treatment significantly decreased bmi1 expression, followed by increased P16INK4a expression. A knockdown of bmi1 induced increased p16INK4a expression, decreased cell proliferation, and increased cellular senescence. In conclusion...

Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence

Cosme-Blanco, Wilfredo; Shen, Mei-Feng; Lazar, Alexander J F; Pathak, Sen; Lozano, Guillermina; Multani, Asha S; Chang, Sandy
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Dysfunctional telomeres induce p53-dependent cellular senescence and apoptosis, but it is not known which function is more important for tumour suppression in vivo. We used the p53 R172P knock-in mouse, which is unable to induce apoptosis but retains intact cell-cycle arrest and cellular senescence pathways, to show that spontaneous tumorigenesis is potently repressed in Terc −/− p53 R172P mice. Tumour suppression is accompanied by global induction of p53, p21 and the senescence marker senescence-associated-β-galactosidase. By contrast, cellular senescence was unable to suppress chemically induced skin carcinomas. These results indicate that suppression of spontaneous tumorigenesis by dysfunctional telomeres requires the activation of the p53-dependent cellular senescence pathway.

Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis

Chen, Zhenbang; Trotman, Lloyd C.; Shaffer, David; Lin, Hui-Kuan; Dotan, Zohar A.; Niki, Masaru; Koutcher, Jason A.; Scher, Howard I.; Ludwig, Thomas; Gerald, William; Cordon-Cardo, Carlos; Pandolfi, Pier Paolo
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 04/08/2005 Português
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Cellular senescence has been theorized to oppose neoplastic transformation triggered by activation of oncogenic pathways in vitro1–3, but the relevance of senescence in vivo has not been established. The PTEN and p53 tumour suppressors are among the most commonly inactivated or mutated genes in human cancer including prostate cancer4,5. Although they are functionally distinct, reciprocal cooperation has been proposed, as PTEN is thought to regulate p53 stability, and p53 to enhance PTEN transcription6–10. Here we show that conditional inactivation of Trp53 in the mouse prostate fails to produce a tumour phenotype, whereas complete Pten inactivation in the prostate triggers non-lethal invasive prostate cancer after long latency. Strikingly, combined inactivation of Pten and Trp53 elicits invasive prostate cancer as early as 2 weeks after puberty and is invariably lethal by 7 months of age. Importantly, acute Pten inactivation induces growth arrest through the p53-dependent cellular senescence pathway both in vitro and in vivo, which can be fully rescued by combined loss of Trp53. Furthermore, we detected evidence of cellular senescence in specimens from early-stage human prostate cancer. Our results demonstrate the relevance of cellular senescence in restricting tumorigenesis in vivo and support a model for cooperative tumour suppression in which p53 is an essential failsafe protein of Pten-deficient tumours.

Accelerated cellular senescence in degenerate intervertebral discs: a possible role in the pathogenesis of intervertebral disc degeneration

Le Maitre, Christine Lyn; Freemont, Anthony John; Hoyland, Judith Alison
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
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Current evidence implicates intervertebral disc degeneration as a major cause of low back pain, although its pathogenesis is poorly understood. Numerous characteristic features of disc degeneration mimic those seen during ageing but appear to occur at an accelerated rate. We hypothesised that this is due to accelerated cellular senescence, which causes fundamental changes in the ability of disc cells to maintain the intervertebral disc (IVD) matrix, thus leading to IVD degeneration. Cells isolated from non-degenerate and degenerate human tissue were assessed for mean telomere length, senescence-associated β-galactosidase (SA-β-gal), and replicative potential. Expression of P16INK4A (increased in cellular senescence) was also investigated in IVD tissue by means of immunohistochemistry. RNA from tissue and cultured cells was used for real-time polymerase chain reaction analysis for matrix metalloproteinase-13, ADAMTS 5 (a disintegrin and metalloprotease with thrombospondin motifs 5), and P16INK4A. Mean telomere length decreased with age in cells from non-degenerate tissue and also decreased with progressive stages of degeneration. In non-degenerate discs, there was an age-related increase in cellular expression of P16INK4A. Cells from degenerate discs (even from young patients) exhibited increased expression of P16INK4A...

SIRT1 Overexpression Antagonizes Cellular Senescence with Activated ERK/S6k1 Signaling in Human Diploid Fibroblasts

Huang, Jing; Gan, Qini; Han, Limin; Li, Jian; Zhang, Hai; Sun, Ying; Zhang, Zongyu; Tong, Tanjun
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 05/03/2008 Português
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Sir2, a NAD-dependent deacetylase, modulates lifespan in yeasts, worms and flies. The SIRT1, mammalian homologue of Sir2, regulates signaling for favoring survival in stress. But whether SIRT1 has the function to influence cell viability and senescence under non-stressed conditions in human diploid fibroblasts is far from unknown. Our data showed that enforced SIRT1 expression promoted cell proliferation and antagonized cellular senescence with the characteristic features of delayed Senescence-Associated β-galactosidase (SA-β-gal) staining, reduced Senescence-Associated Heterochromatic Foci (SAHF) formation and G1 phase arrest, increased cell growth rate and extended cellular lifespan in human fibroblasts, while dominant-negative SIRT1 allele (H363Y) did not significantly affect cell growth and senescence but displayed a bit decreased lifespan.. Western blot results showed that SIRT1 reduced the expression of p16INK4A and promoted phosphorylation of Rb. Our data also exposed that overexpression of SIRT1 was accompanied by enhanced activation of ERK and S6K1 signaling. These effects were mimicked in both WI38 cells and 2BS cells by concentration-dependent resveratrol, a SIRT1 activator. It was noted that treatment of SIRT1-.transfected cells with Rapamycin...

Knockout of Ku86 accelerates cellular senescence induced by high NaCl

Dmitrieva, Natalia I.; Chen, Hua Tang; Nussenzweig, André; Burg, Maurice B.
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Publicado em 12/02/2009 Português
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NaCl induces DNA breaks, thus leading to cellular senescence. Here we showed that Ku86 deficiency accelerated the high NaCl-induced cellular senescence. We find that 1) high NaCl induces rapid cellular senescence in Ku86 deficient (xrs5) cells, 2) Ku86 deficiency shortens lifespan of C. elegans in high NaCl, and 3) cellular senescence is greatly accelerated in renal inner medullas of Ku86-/- mice. Further, although water balance is known to be compromised in old mice, this occurs at much earlier age in Ku86-/- mice. When subjected to mild water restriction, 3 month old Ku86-/-, but not Ku86+/+, mice rapidly become dehydrated as evidenced by decrease in body weight, increased production of antidiuretic hormone, increased urine osmolality and decreased urine volume. The deficiency in water balance does not occur in Ku86+/+mice until they are much older (14 months). We conclude that Ku86 deficiency accelerates high NaCl-induced cellular senescence...

Ionizing Radiation Induces Cellular Senescence of Articular Chondrocytes via Negative Regulation of SIRT1 by p38 Kinase*

Hong, Eun-Hee; Lee, Su-Jae; Kim, Jae-Sung; Lee, Kee-Ho; Um, Hong-Duck; Kim, Jae-Hong; Kim, Song-Ja; Kim, Jong-Il; Hwang, Sang-Gu
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Português
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Radiotherapy is increasingly used in the treatment of joint diseases, but limited information is available on the effects of radiation on cartilage. Here, we characterize the molecular mechanisms leading to cellular senescence in irradiated primary cultured articular chondrocytes. Ionizing radiation (IR) causes activation of ERK, in turn generating intracellular reactive oxygen species (ROS) with induction of senescence-associated β-galactosidase (SA-β-gal) activity. ROS activate p38 kinase, which further promotes ROS generation, forming a positive feedback loop to sustain ROS-p38 kinase signaling. The ROS inhibitors, nordihydroguaiaretic acid and GSH, suppress phosphorylation of p38 and cell numbers positive for SA-β-gal following irradiation. Moreover, inhibition of the ERK and p38 kinase pathways leads to blockage of IR-induced SA-β-gal activity via reduction of ROS generation. Although JNK is activated by ROS, this pathway is not associated with cellular senescence of chondrocytes. Interestingly, IR triggers down-regulation of SIRT1 protein expression but not the transcript level, indicative of post-transcriptional cleavage of the protein. SIRT1 degradation is markedly blocked by SB203589 or MG132 after IR treatment, suggesting that cleavage occurs as a result of binding with p38 kinase...

p35 Is Required for CDK5 Activation in Cellular Senescence*

Mao, Daqin; Hinds, Philip W.
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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The retinoblastoma tumor suppressor gene (RB-1) is a key regulator of cellular senescence. Expression of the retinoblastoma protein (pRB) in human tumor cells that lack it results in senescence-like changes. The induction of the senescent phenotype by pRB requires the postmitotic kinase CDK5, the best known function of which is in neuronal development and postmitotic neuronal activities. Activation of CDK5 in neurons depends on its activators p35 and p39; however, little is known about how CDK5 is activated in non-neuronal senescent cells. Here we report that p35 is required for the activation of CDK5 in the process of cellular senescence. We demonstrate that: (i) p35 is expressed in osteosarcoma cells, (ii) p35 is required for CDK5 activation induced by pRB during senescence, (iii) p35 is required for the senescent morphological changes in which CDK5 is known to be involved as well as for expression of the senescence secretome, and (iv) p35 is up-regulated in senescing cells. Taken together, these results suggest that p35 is at least one of the activators of CDK5 that is mobilized in the process of cellular senescence, which may provide insight into cancer cell proliferation and future cancer therapeutics.

Cellular Senescence as a Target in Cancer Control

Vergel, Mar; Marin, Juan J.; Estevez, Purificacion; Carnero, Amancio
Fonte: SAGE-Hindawi Access to Research Publicador: SAGE-Hindawi Access to Research
Tipo: Artigo de Revista Científica
Publicado em 30/12/2010 Português
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Somatic cells show a spontaneous decline in growth rate in continuous culture. This is not related to elapsed time but to an increasing number of population doublings, eventually terminating in a quiescent but viable state termed replicative senescence. These cells are commonly multinucleated and do not respond to mitogens or apoptotic stimuli. Cells displaying characteristics of senescent cells can also be observed in response to other stimuli, such as oncogenic stress, DNA damage, or cytotoxic drugs and have been reported to be found in vivo. Most tumors show unlimited replicative potential, leading to the hypothesis that cellular senescence is a natural antitumor program. Recent findings suggest that cellular senescence is a natural mechanism to prevent undesired oncogenic stress in somatic cells that has been lost in malignant tumors. Given that the ultimate goal of cancer research is to find the definitive cure for as many tumor types as possible, exploration of cellular senescence to drive towards antitumor therapies may decisively influence the outcome of new drugs. In the present paper, we will review the potential of cellular senescence to be used as target for anticancer therapy.

Never-ageing cellular senescence

Ogrunc, Müge; Fagagna, Fabrizio d’Adda di
Fonte: Elsevier Science Ltd Publicador: Elsevier Science Ltd
Tipo: Artigo de Revista Científica
Publicado em /07/2011 Português
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Cellular senescence was historically discovered as a form of cellular ageing of in vitro cultured cells. It has been under the spotlight following the evidence of oncogene-induced senescence in vivo and its role as a potent tumour suppressor mechanism. Presently, a PubMed search using keywords ‘cellular senescence and cancer’ reveals 8398 number of references (by April 2011) showing that while our knowledge of senescence keeps expanding, the complexity of the phenomenon keeps us – researchers in the field of cancer biology – fascinated and busy. In this short review, we summarise the many cellular pathways leading to cellular senescence and we discuss the latest experimental evidence and the questions emerging in the field.

Cellular senescence and tumor suppressor gene p16

Rayess, Hani; Wang, Marilene B.; Srivatsan, Eri S.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Cellular senescence is an irreversible arrest of cell growth. Biochemical and morphological changes occur during cellular senescence, including the formation of a unique cellular morphology such as flattened cytoplasm. Function of mitochondria, endoplasmic reticulum and lysosomes are affected resulting in the inhibition of lysosomal and proteosomal pathways. Cellular senescence can be triggered by a number of factors including, aging, DNA damage, oncogene activation and oxidative stress. While the molecular mechanism of senescence involves p16 and p53 tumor suppressor genes and telomere shortening, this review is focused on the mechanism of p16 control. The p16 mediated senescence acts through the retinoblastoma (Rb) pathway inhibiting the action of the cyclin dependant kinases leading to G1 cell cycle arrest. Rb is maintained in a hypophosphorylated state resulting in the inhibition of transcription factor E2F1. Regulation of p16 expression is complex and involves epigenetic control and multiple transcription factors. PRC1 (Pombe repressor complex 1) and PRC2 (Pombe repressor complex 2) proteins and histone deacetylases play an important role in the promoter hypermethylation for suppressing p16 expression. While transcription factors YY1 and Id1 suppress p16 expression...

Cellular Senescence and Cancer Chemotherapy Resistance

Gordon, Ryan R.; Nelson, Peter S.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Innate or acquired resistance to cancer therapeutics remains an important area of biomedical investigation that has clear ramifications for improving cancer specific death rates. Importantly, clues to key resistance mechanisms may lie in the well-orchestrated and highly conserved cellular and systemic responses to injury and stress. Many anti-neoplastic therapies typically rely on DNA damage, which engages potent DNA damage response signaling pathways that culminate in apoptosis or growth arrest at checkpoints to allow for damage repair. However, an alternative cellular response, senescence, can also be initiated when challenged with these internal/external pressures and in ideal situations acts as a self-protecting mechanism. Senescence-induction therapies are an attractive concept in that they represent a normal, highly conserved and commonly-invoked tumor-suppressing response to overwhelming genotoxic stress or oncogene activation. Yet, such approaches should ensure that senescence by-pass or senescence re-emergence does not occur, as emergent cells appear to have highly drug resistant phenotypes. Further, cell non-autonomous senescence responses may contribute to therapy-resistance in certain circumstances. Here we provide an overview of mechanisms by which cellular senescence plausibly contributes to therapy resistance and concepts by which senescence responses can be influenced to improve cancer treatment outcomes.

The CEACAM1 tumor suppressor is an ATM and p53-regulated gene required for the induction of cellular senescence by DNA damage

Sappino, A-P; Buser, R; Seguin, Q; Fernet, M; Lesne, L; Gumy-Pause, F; Reith, W; Favaudon, V; Mandriota, S J
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
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The p53 tumor-suppressor protein has a key role in the induction of cellular senescence, an important barrier to cancer development. However, very little is known about the physiological mediators of cellular senescence induced by p53. CEACAM1 is an immunoglobulin superfamily member whose expression is frequently lost in human tumors and exhibits tumor-suppressor features in several experimental systems, including Ceacam1 knockout mice. There is currently little understanding of the pathways and mechanisms by which CEACAM1 exerts its tumor-suppressor function. Here we report that CEACAM1 is strongly upregulated during the cellular response to DNA double-strand breaks (DSBs) starting from the lowest doses of DSB inducers used, and that upregulation is mediated by the ataxia telangiectasia mutated (ATM)/p53 pathway. Stable silencing of CEACAM1 showed that CEACAM1 is required for p53-mediated cellular senescence, but not initial cell growth arrest, in response to DNA damage. These findings identify CEACAM1 as a key component of the ATM/p53-mediated cellular response to DNA damage, and as a tumor suppressor mediating cellular senescence downstream of p53.

The impact of cellular senescence in cancer therapy: is it true or not?

Zhang, Yi; Yang, Jin-ming
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
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Cellular senescence is defined as the physiological program of terminal growth arrest, which can be triggered by various endogenous or exogenous stress signals. Cellular senescence can be induced in response to oncogenic activation and acts as a barrier to tumorigenesis. Moreover, tumor cells can undergo senescence when exposed to chemotherapeutic agents. In addition to suppressing tumorigenesis, senescent cells remain metabolically active and may contribute to tumor formation and to therapy resistance. In the current review, we discuss the molecular regulation of cellular senescence, the potential implications of senescence in human cancers, and the possibility of exploiting cellular senescence for the treatment of cancers.

P21-PARP-1 Pathway Is Involved in Cigarette Smoke-Induced Lung DNA Damage and Cellular Senescence

Yao, Hongwei; Sundar, Isaac K.; Gorbunova, Vera; Rahman, Irfan
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 11/11/2013 Português
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Persistent DNA damage triggers cellular senescence, which may play an important role in the pathogenesis of cigarette smoke (CS)-induced lung diseases. Both p21CDKN1A (p21) and poly(ADP-ribose) polymerase-1 (PARP-1) are involved in DNA damage and repair. However, the role of p21-PARP-1 axis in regulating CS-induced lung DNA damage and cellular senescence remains unknown. We hypothesized that CS causes DNA damage and cellular senescence through a p21-PARP-1 axis. To test this hypothesis, we determined the levels of γH2AX (a marker for DNA double-strand breaks) as well as non-homologous end joining proteins (Ku70 and Ku80) in lungs of mice exposed to CS. We found that the level of γH2AX was increased, whereas the level of Ku70 was reduced in lungs of CS-exposed mice. Furthermore, p21 deletion reduced the level of γH2AX, but augmented the levels of Ku70, Ku80, and PAR in lungs by CS. Administration of PARP-1 inhibitor 3-aminobenzamide increased CS-induced DNA damage, but lowered the levels of Ku70 and Ku80, in lungs of p21 knockout mice. Moreover, 3-aminobenzamide increased senescence-associated β-galactosidase activity, but decreased the expression of proliferating cell nuclear antigen in mouse lungs in response to CS. Interestingly...

Bacterial intoxication evokes cellular senescence with persistent DNA damage and cytokine signalling

Blazkova, Hana; Krejcikova, Katerina; Moudry, Pavel; Frisan, Teresa; Hodny, Zdenek; Bartek, Jiri
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
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Cytolethal distending toxins (CDTs) are proteins produced and secreted by facultative pathogenic strains of Gram-negative bacteria with potentially genotoxic effects. Mammalian cells exposed to CDTs undergo cell type-dependent cell-cycle arrest or apoptosis; however, the cell fate responses to such intoxication are mechanistically incompletely understood. Here we show that both normal and cancer cells (BJ, IMR-90 and WI-38 fibroblasts, HeLa and U2-OS cell lines) that survive the acute phase of intoxication by Haemophilus ducreyi CDT possess the hallmarks of cellular senescence. This characteristic phenotype included persistently activated DNA damage signalling (detected as 53BP1/γH2AX+ foci), enhanced senescence-associated β-galactosidase activity, expansion of promyelocytic leukaemia nuclear compartments and induced expression of several cytokines (especially interleukins IL-6, IL-8 and IL-24), overall features shared by cells undergoing replicative or premature cellular senescence. We conclude that analogous to oncogenic, oxidative and replicative stresses, bacterial intoxication represents another pathophysiological stimulus that induces premature senescence, an intrinsic cellular response that may mechanistically underlie the ‘distended’ morphology evoked by CDTs. Finally...

Critical pathways in cellular senescence and immortalization revealed by gene expression profiling

Fridman, AL; Tainsky, MA
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Bypassing cellular senescence and becoming immortal is a prerequisite step in the tumorigenic transformation of a cell. It has long been known that loss of a key tumor suppressor gene, such as p53, is necessary, but not sufficient, for spontaneous cellular immortalization. Therefore, there must be additional mutations and/or epigenetic alterations required for immortalization to occur. Early work on these processes included somatic cell genetic studies to estimate the number of senescence genes, and microcell-mediated transfer of chromosomes into immortalized cells to identify putative senescence-inducing genetic loci. These principal studies laid the foundation for the field of senescence/immortalization, but were labor intensive and the results were somewhat limited. The advent of gene expression profiling and bioinformatics analysis greatly facilitated the identification of genes and pathways that regulate cellular senescence/immortalization. In this review, we present the findings of several gene expression profiling studies and supporting functional data, where available. We identified universal genes regulating senescence/immortalization and found that the key regulator genes represented six pathways: the cell cycle pRB/p53, cytoskeletal...

ACUTE DYSKERIN DEPLETION TRIGGERS CELLULAR SENESCENCE AND RENDERS OSTEOSARCOMA CELLS RESISTANT TO GENOTOXIC STRESS-INDUCED APOPTOSIS

Lin, Ping; Mobasher, Maral E.; Alawi, Faizan
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Dyskerin is a conserved, nucleolar RNA-binding protein implicated in an increasing array of fundamental cellular processes. Germline mutation in the dyskerin gene (DKC1) is the cause of X-linked dyskeratosis congenita. Conversely, wild-type dyskerin is overexpressed in sporadic cancers, and high-levels may be associated with poor prognosis. It was previously reported that acute loss of dyskerin function via siRNA-mediated depletion slowed the proliferation of transformed cell lines. However, the mechanisms remained unclear. Using human U2OS osteosarcoma cells, we show that siRNA-mediated dyskerin depletion induced cellular senescence as evidenced by proliferative arrest, senescence-associated heterochromatinization and a senescence-associated molecular profile. Senescence can render cells resistant to apoptosis. Conversely, chromatin relaxation can reverse the repressive effects of senescence-associated heterochromatinization on apoptosis. To this end, genotoxic stress-induced apoptosis was suppressed in dyskerin-depleted cells. In contrast, agents that induce chromatin relaxation, including histone deacetylase inhibitors and the DNA intercalator chloroquine, sensitized dyskerin-depleted cells to apoptosis. Dyskerin is a core component of the telomerase complex and plays an important role in telomere homeostasis. Defective telomere maintenance resulting in premature senescence is thought to primarily underlie the pathogenesis of X-linked DC. Since U2OS cells are telomerase-negative...

Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging

Ziegler, Dorian V; Wiley, Christopher D; Velarde, Michael C
Fonte: BlackWell Publishing Ltd Publicador: BlackWell Publishing Ltd
Tipo: Artigo de Revista Científica
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Cellular senescence is a process that results from a variety of stresses, leading to a state of irreversible growth arrest. Senescent cells accumulate during aging and have been implicated in promoting a variety of age-related diseases. Mitochondrial stress is an effective inducer of cellular senescence, but the mechanisms by which mitochondria regulate permanent cell growth arrest are largely unexplored. Here, we review some of the mitochondrial signaling pathways that participate in establishing cellular senescence. We discuss the role of mitochondrial reactive oxygen species (ROS), mitochondrial dynamics (fission and fusion), the electron transport chain (ETC), bioenergetic balance, redox state, metabolic signature, and calcium homeostasis in controlling cellular growth arrest. We emphasize that multiple mitochondrial signaling pathways, besides mitochondrial ROS, can induce cellular senescence. Together, these pathways provide a broader perspective for studying the contribution of mitochondrial stress to aging, linking mitochondrial dysfunction and aging through the process of cellular senescence.