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Results for “Cellular Senescence”

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PubMed2004

Role of IFI 16 in cellular senescence of human fibroblasts.

Defects in interferon (IFN) signaling that result in loss of expression of IFN-inducible proteins are associated with cellular immortalization, an important early event in the development of human cancer. Here we report that loss of IFN-inducible IFI 16 expression in human fibroblasts allows bypass of cellular senescence. We found that levels of IFI 16 mRNA and protein were higher in human old versus young fibroblasts and immortalization of fibroblasts with telomerase resulted in decreased expression of IFI 16. Moreover, overexpression of IFI 16 in immortalized fibroblasts strongly inhibited cell proliferation. Interestingly, knockdown of IFI 16 expression in fibroblasts inhibited p53-mediated transcription, downregulated p21(WAF1) expression, and extended the proliferation potential. Importantly, treatment of immortal cell lines with 5-aza-2'-deoxycytidine, an inhibitor of DNA methyltransferase, resulted in upregulation of IFI 16. Our observations support the idea that increased levels of IFI 16 in older populations of human fibroblasts contribute to cellular senescence.

Cell Line, Transformed↗

PubMed1997

Mechanisms of cellular senescence.

Aging is a near universal process, yet the molecular mechanisms that underlie cellular senescence have remained elusive. Recent progress in determining the roles of various genetic influences in controlling the rate of cellular aging has made this an exciting time in aging research. Genetic screens designed to isolate long-lived mutants in Saccharomyces cerevisiae and Caenorhabditis elegans have implicated factors involved in transcriptional silencing and the dauer pathway in the control of aging. The gene responsible for Werner's syndrome, a disease with symptoms of premature aging, was isolated and found to be a member of the RecQ subfamily of DNA helicases. The regulation of telomere length and its role in senescence and cellular immortalization has been found to be more complex than expected. In C. elegans, mutations have been isolated in maternal-effect genes that presumably control its biological clocks and can dramatically extend its lifespan. Indeed, aging research within the past year has implicated a variety of mechanisms ranging from the control of gene expression, stress resistance, and DNA metabolism to the overall 'rate of living'.

Animals↗

PubMed2006

Downregulation of protein kinase CKII is associated with cellular senescence.

Protein kinase CKII (CKII) plays a critical role in cell growth and proliferation. In this study, we examine how CKII activity is regulated during cellular senescence. Our results demonstrate that CKII activity apparently decreases during both replicative and H2O2-induced senescence in human diploid fibroblast IMR-90 cells. The mRNA and protein levels of CKIIalpha decreases significantly during replicative and H2O2-induced senescence, while only slight reduction in those of CKIIbeta is observed during replicative senescence. Treatment of IMR-90 cells with CKII inhibitors 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole and apigenin led cells to acquire a senescent phenotype as judged by the senescence-associated beta-galactosidase marker and overexpression of p53 and p21(Waf-1). Knockdown of CKIIalpha in IMR-90 cells by RNA interference also dramatically induced the senescent phenotype. In parallel, CKII activity was transcriptional downregulated in rat liver and testis with advancing age. Taken together, these results suggest that downregulation of CKII activity is tightly associated not only with cellular senescence but also with organism aging.

Aging↗

PubMed2000

Enhanced oxidative stress and accelerated cellular senescence in glucose-6-phosphate dehydrogenase (G6PD)-deficient human fibroblasts.

Glucose-6-phosphate dehydrogenase (G6PD) is involved in the generation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and the maintenance of the cellular redox balance. The biological effects of G6PD deficiency in nucleated cells were studied using G6PD-deficient human foreskin fibroblasts (HFF). In contrast to that of normal HFF, the doubling time of G6PD-deficient cells increased readily from population doubling level (PDL) 15 to 63. This was accompanied by a significant increase in the percentage of G(1) cells. The slow-down in growth preceded an early entry of these cells into a nondividing state reminiscent of cellular senescence. These cells exhibited a significant increase in level of senescence-associated beta-galactosidase (SA-beta-gal) staining. The importance of G6PD activity in cell growth was corroborated by the finding that ectopic expression of active G6PD in the deficient cells prevented their growth retardation and early onset of senescence. Mechanistically, the enhanced fluorescence in dichlorofluorescin (H(2)DCF)-stained G6PD-deficient cells suggests the possible involvement of reactive oxygen species in senescence. Taken together, our results show that G6PD deficiency predisposes human fibroblasts to retarded growth and accelerated cellular senescence. Moreover, G6PD-deficient HFF provides a useful model system for delineating the effects of redox alterations on cellular processes.

Cell Cycle↗

PubMed2007

p63, cellular senescence and tumor development.

Deficiency of p63, a p53-related protein, causes severe defects in epithelial morphogenesis. Studies of p63-compromised mouse models reveal that p63 deficiency induces cellular senescence both in cultured cells and in vivo, through regulation p19(Arf)/p53 and p16(Ink4a)/Rb pathways. An extensive tumor study of p63-compromised mice demonstrated that p63 deficiency does not predispose to, but rather protects from, tumor development. These findings further implicate p63 as a negative regulator of the tumor suppressive mechanism of cellular senescence.

Animals↗

PubMed1999

Decreased expression and activity of the immediate-early growth response (Egr-1) gene product during cellular senescence.

Human diploid fibroblasts (HDFs) undergo a limited number of population doublings in culture before reaching the end of their proliferative life span, an event termed in vitro cellular senescence. Considerable evidence suggests that altered expression of key genes involved in the mitogenic response may be responsible for the inability of senescent cells to proliferate. Here we examined the expression and activity of the early growth response-1 (egr-1) gene, an "immediate-early" gene that is believed to link extracellular mitogenic signals to cell-cycle progression. We found that egr-1 was strongly downregulated in senescent HDFs at the level of mRNA, protein, and DNA binding activity. Decreased DNA binding activity of Egr-1 in vitro corresponded to decreased transcriptional activation in vivo. To further understand the mechanism of egr-1 downregulation, we examined the potential role of the serum response elements (SREs) present in the egr-1 promoter. Electrophoretic mobility shift studies using young and old cell nuclear extracts showed a marked decrease in serum response factor (SRF) binding activity to the SRE in old compared to young cells. Loss of SRF binding activity has been correlated with the loss of expression of another growth-related immediate-early gene (c-fos). These results suggest a common mechanism for the downregulation of c-fos, egr-1, and other SRE-dependent, mitogen-responsive genes during cellular senescence.

Cells, Cultured↗

PubMed1995

[Cellular senescence and survival of T lymphocytes].

In order to study cellular senescence in T lymphocytes and its link with aging, we have undertaken long-term cultures from adult individuals (aged from 20 to 40) and centenarians. The proliferative advantage of CD4+ over CD8+ T cells is reversed after the second stimulation. Periodically stimulated cultures remained exponentially growing during nearly 200 days, whereas 2 of them that were continued for 300 days stopped proliferating. However, once this phase of senescence is reached, the cells do not die out. Six other cultures remained viable for 34 months without proliferation but with conservation of the cell number. Three of these cultures have clonal karyotypic abnormalities: trisomy 2 and telomeric fusions.

Adult↗

PubMed1991

Tumor suppression by chromosome 11 is not due to cellular senescence.

Previous hybrid studies involving fusion of normal with immortal human cells indicated that the phenotype of cellular senescence is dominant and that immortality results from recessive changes in normal growth regulatory genes. We have further assigned 28 different immortal human cell lines to at least four complementation groups for indefinite division. In order to identify the chromosomes involved in regulating cell proliferation, we have introduced single human chromosomes by microcell fusion into immortal human cells representative of the different complementation groups. Our results demonstrate that the introduction of chromosome 11, implicated in tumor suppression, does not cause cellular senescence in three different immortal human cell lines tested.

Animals↗

PubMed1999

Two posttranscriptional pathways that regulate p21(Cip1/Waf1/Sdi1) are identified by HPV16-E6 interaction and correlate with life span and cellular senescence.

The p21((Cip1/Waf1/Sdi1)) protein is a cyclin-dependent kinase inhibitor that is induced in normal human fibroblasts (NHF) following DNA damage, following serum stimulation, and at cellular senescence. Expression of the human papilloma virus 16 E6 oncoprotein in NHF cells results in the loss of the p21 protein, independent of mRNA level under most conditions. The p21 protein levels in NHF-E6 cells remained low following DNA damage or serum stimulation even though mRNA levels increased. In contrast, the p21 protein was transiently induced in NHF-E6 cells at the onset of cellular senescence. Expression of the E6 oncoprotein in transformed cells had no effect on p21 protein levels. This demonstrates that two posttranscriptional pathways regulate expression of p21 protein in NHF cells under different conditions. Disruption of posttranscriptional regulation is correlated with extension of life span, altered cell fate, and transformation.

Cell Transformation, Viral↗

PubMed2006

Regulation of cellular senescence by Rb2/p130.

Growth regulatory functions of Rb2/p130, which aim at a sustained arrest such as in quiescent or differentiated cells, qualify the protein also to act as a central regulator of growth arrest in cellular senescence. In this respect, Rb2/p130 functions are connected to signaling pathways induced by p53, which is a master regulator in cellular senescence. Here, we summarize the pathways, which specify pRb2/p130 to control this arrest program and distinguish its functions from those of pRb/p105.

Animals↗

PubMed2004

Regulation of cellular senescence and p16(INK4a) expression by Id1 and E47 proteins in human diploid fibroblast.

Id1, a member of Id family of helix-loop-helix transcriptional regulatory proteins, is implicated in cellular senescence by repressing p16(INK4a) expression, but the mechanisms and cellular effects in human diploid fibroblasts remain unknown. Here we analyzed the patterns of p16(INK4a) and Id1 expression during the lifespan of 2BS cells and presented the inverse correlation between these two proteins. Immunoprecipitation assays demonstrated the presence of endogenous interaction of Id1 and E47 proteins that was strong in young 2BS cells and weakened during replicative senescence and, thereby, influenced the transcription activation of p16(INK4a) by E47. Furthermore, we found that E47 protein could bind to the E-box-containing region in p16(INK4a) promoter in senescent cells by chromatin immunoprecipitation analyses, suggesting that E47 is indeed ultimately involved in the regulation of p16(INK4a) transcription in vivo. Silencing Id1 expression in young cells by RNA interference induced an increased p16(INK4a) level and premature cellular senescence, whereas silencing E47 expression inhibited the expression of p16(INK4a) and delayed the onset of senescent phenotype. The present study demonstrated not only the capacity of Id1 to regulate p16(INK4a) gene expression by E47, but also the phenotypic consequence of the regulation on cellular senescence, moreover, raised the possibility of Id1-specific gene silencing for human cancer therapy.

Base Sequence↗

PubMed2005

Down-regulation of a forkhead transcription factor, FOXO3a, accelerates cellular senescence in human dermal fibroblasts.

The signaling pathway of insulin/insulin-like growth factor/phosphatidylinositol-3 kinase/Akt/forkhead transcription factors is known to control life span and senescence in organisms ranging from yeast to mice. The FOXO family of forkhead transcription factors, FOXO1, FOXO3a, and FOXO4, play a critical role in this signal transduction pathway. However, the impact of FOXO3a activation on life span of primary cultured human dermal fibroblasts (HDFs) is unknown. To investigate the role of FOXO3a in the regulation of cellular senescence, we prepared FOXO3a-siRNA stable HDFs. We found that the down-regulation of FOXO3a RNA and protein in HDFs induced many senescent phenotypes, including changes in cell morphology, increases in population doubling times, senescence-associated beta-galactosidase staining and the cellular reactive oxygen species, and up-regulation of p53/p21 protein expression. Our data provide evidence of the key role of FOXO3a transcription factor as a mediator of cellular senescence in HDFs, and suggest that the mechanism of senescence is conserved in HDFs.

Cells, Cultured↗

PubMed2006

Prohibitin facilitates cellular senescence by recruiting specific corepressors to inhibit E2F target genes.

Prohibitin is a growth regulatory gene that has pleiotropic functions in the nucleus, mitochondria, and cytoplasmic compartments. Earlier studies had proposed a role for prohibitin in modulating cellular senescence, but the underlying mechanisms remain unknown. Here we show that senescence induced by DNA-damaging agents causes the localization of prohibitin to specific heterochromatic foci. Prohibitin could bind to heterochromatin protein 1 (HP1) family proteins and colocalized with HP1gamma in senescence-associated heterochromatic foci. Further, HP1gamma could synergize with prohibitin to repress E2F1-mediated transcriptional activity. The depletion of prohibitin by small interfering RNA or antisense techniques led to a reduction in the senescent phenotype, correlating with a reduced expression of senescence-associated beta-galactosidase and fewer numbers of senescence-associated heterochromatic foci. Chromatin immunoprecipitation assays showed that prohibitin is needed for the recruitment of HP1gamma to E2F1-regulated proliferative promoters, leading to their repression. The ablation of prohibitin prevented the recruitment of HPIgamma, but not Suv39H, to the promoters upon senescence. Prohibitin-mediated recruitment of HP1gamma occurred in only senescent cells, not in quiescent cells; thus, there is a dichotomy in the recruitment of different corepressors by prohibitin, depending on the type of growth arrest. These studies show that prohibitin plays a vital role in inducing cellular senescence.

Cell Line, Tumor↗

PubMed1991

A role for both RB and p53 in the regulation of human cellular senescence.

We present evidence for the possible involvement of both the RB and p53 proteins in the regulation of cellular senescence. Human fibroblasts immortalized with an inducible SV40 T-antigen become senescent following the de-induction of T-antigen. Plasmids expressing an alternative source of intact T-antigen restore proliferation but T-antigen deletion mutants lacking either the RB or p53 binding domains are unable to do so. Similarly, combinations of adenovirus E1A + E1B or human papillomavirus E6 + E7 genes are able to replace T-antigen functions and permit cell proliferation, whereas the individual genes do not. These results are discussed in terms of a two-stage model for the escape from in vitro cellular senescence.

Adenoviruses, Human↗

PubMed2006

Cellular senescence in naevi and immortalisation in melanoma: a role for p16?

Cellular senescence, the irreversible proliferative arrest seen in somatic cells after a limited number of divisions, is considered a crucial barrier to cancer, but direct evidence for this in vivo was lacking until recently. The best-known form of human cell senescence is attributed to telomere shortening and a DNA-damage response through p53 and p21. There is also a more rapid form of senescence, dependent on the p16-retinoblastoma pathway. p16 (CDKN2A) is a known melanoma susceptibility gene. Here, we use retrovirally mediated gene transfer to confirm that the normal form of senescence in cultured human melanocytes involves p16, since disruption of the p16/retinoblastoma pathway is required as well as telomerase activation for immortalisation. Expression (immunostaining) patterns of senescence mediators and markers in melanocytic lesions provide strong evidence that cell senescence occurs in benign melanocytic naevi (moles) in vivo and does not involve p53 or p21 upregulation, although p16 is widely expressed. In comparison, dysplastic naevi and early (radial growth-phase, RGP) melanomas show less p16 and some p53 and p21 immunostaining. All RGP melanomas expressed p21, suggesting areas of p53-mediated senescence, while most areas of advanced (vertical growth-phase) melanomas lacked both p16 and p21, implying escape from both forms of senescence (immortalisation). Moreover, nuclear p16 but not p21 expression can be induced in human melanocytes by oncogenic BRAF, as found in around 80% of naevi. We conclude that cell senescence can form a barrier to melanoma development. This also provides a potential explanation of why p16 is a melanoma suppressor gene.

Cell Survival↗

PubMed1994

Identification of a defect in the phospholipase D/diacylglycerol pathway in cellular senescence.

Normal cells become senescent in culture after a limited number of population doublings becoming unable to respond to mitogens. This raises the possibility of defects in mitogenic signaling pathways in cellular senescence. In contrast to young human diploid fibroblasts (HDF), their senescent counterparts failed to undergo protein kinase C translocation in response to serum stimulation. On the other hand, phorbol 12-myristate 13-acetate was equally active in inducing protein kinase C translocation in young and senescent HDF. This suggested a defect in generation of the endogenous activator of protein kinase C, diacylglycerol. Stimulation of young HDF with serum resulted in 3-4-fold generation of diacylglycerol (DAG). In contrast, senescent cells displayed insignificant DAG formation in response to serum. The mechanism of DAG generation was investigated next. In young HDF, serum induced a 5-fold activation of the phospholipase D (PLD) pathway as measured by the incorporation of exogenous ethanol into phosphatidylethanol, which is a measure of the transphosphatidylation reaction of PLD. In contrast, PLD in senescent cells was not activated by serum. Since senescent cells demonstrate significant elevations in the level of endogenous ceramide, the impact of ceramide on the PLD/DAG pathway was also investigated. A soluble analog of ceramide, C6-ceramide, was found to inhibit serum-stimulated DAG accumulation and PLD activation in young cells. These data demonstrate for the first time a defect in PLD activation in cellular senescence and suggest that ceramide may be responsible for the inhibition of this pathway.

Cells, Cultured↗

PubMed2006

Premature cellular senescence induced by pyocyanin, a redox-active Pseudomonas aeruginosa toxin.

Pseudomonas aeruginosa is an important nosocomial pathogen that can cause acute and chronic infection, particularly of the respiratory system. Pyocyanin is a major P. aeruginosa virulence factor that displays redox activity and induces oxidative stress in cellular systems. The effect of pyocyanin on replicating human pulmonary epithelial (A549) cells was investigated. Cells were exposed to pyocyanin for 24 h and their subsequent growth and development were followed for 7 days. Pyocyanin (5-10 microM) arrested cell growth and resulted in the development of a morphological phenotype consistent with cellular senescence, that is, an enlarged and flattened appearance. The senescent nature of these cells was supported by positive staining for increased lysosomal content and senescence-associated beta-galactosidase activity. All cells treated with pyocyanin (10 microM) converted to the senescent phenotype, which remained stable for up to 7 days. Exposure to pyocyanin at 25 microM or greater resulted in cell death due to apoptosis. A549 cells exposed to pyocyanin generated hydrogen peroxide in a dose-dependent manner and the senescence-inducing effect of pyocyanin was inhibited by the antioxidant, glutathione, suggesting the involvement of reactive oxygen species. The induction of premature cellular senescence by redox-active bacterial toxins may be a hitherto unrecognized aspect of infection pathology and a limiting factor in the tissue repair response to infection.

Antioxidants↗

PubMed2006

Change of potassium current density in rabbit corneal epithelial cells during maturation and cellular senescence.

BACKGROUND: Voltage-gated potassium (K+) channels may participate in cellular developmental regulation, including cell differentiation, proliferation and apoptosis. This study investigated the change of K + current densities in corneal epithelial cells during maturation and cellular senescence. METHODS: New Zealand white rabbits were divided into three age groups: newborn ( 10.0 pF. Using a whole-cell clamp technique, K+ current was recorded and current densities were calculated. Differences in K+ current densities among newborn, young and adult rabbits, as well as differences among small, medium and large cells, were analyzed. RESULTS: We delineated two types of cells manifesting different amplitudes of depolarization-activated K+ outward currents. The averaged current density of type 1 response cells was significantly larger than that of type 2 cells in newborn, young, and adult groups. For newborn epithelial cells, the depolarization-gated outward K+ current density decreased from small to medium to large cells (p = 0.049, at a membrane potential of 140 mV). A similar pattern of change in current density was also delineated for these cell sizes in young and adult rabbit corneal cells (p < 0.001 for both young and adult rabbits). An increase in depolarization-gated outward K+ current density was also delineated from newborn to young to adult rabbits (p < 0.001, p < 0.001 and p < 0.006 for small, medium and large cells, respectively, at a membrane potential of 140 mV). CONCLUSIONS: Corneal epithelial cells expressed K+ channel densities that were distinct from basal to superficial cells and from newborn to adult rabbits.

Animals↗