SEARCH · PubMed Health

Results for “Cellular Senescence”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources

PubMed2006

Cellular senescence and cancer treatment.

Cellular senescence, an irreversible cell-cycle arrest, reflects a safeguard program that limits the proliferative capacity of the cell exposed to endogenous or exogenous stress signals. A number of recent studies have clarified that an acutely inducible form of cellular senescence may act in response to oncogenic activation as a natural barrier to interrupt tumorigenesis at a premalignant level. Paralleling the increasing insights into premature senescence as a tumor suppressor mechanism, a growing line of evidence identifies cellular senescence as a critical effector program in response to DNA damaging chemotherapeutic agents. This review discusses molecular pathways to stress-induced senescence, the interference of a terminal arrest condition with clinical outcome, and the critical overlap between premature senescence and apoptosis as both tumor suppressive and drug-responsive cellular programs.

Animals↗

PubMed1997

Down-regulation of Ku autoantigen, DNA-dependent protein kinase, and poly(ADP-ribose) polymerase during cellular senescence.

During aging and cellular senescence mutations accumulate in genomic and mitochondrial DNA. Ku autoantigens, DNA-dependent protein kinase, and poly (ADP-ribose) polymerase have an essential role in DNA damage recognition. Our purpose was to find out whether cellular senescence of fibroblasts affects the protein components that recognize DNA damage and induce the repair process. We compared presenescent and replicatively senescent human WI-38 fibroblasts with each other and with SV-40 immortalized and serum-deficient quiescent WI-38 cells. Our results showed that replicative senescence significantly decreased the nuclear level of both p70 and p86 components of Ku autoantigen. SV-40 immortalization and cellular quiescence did not affect the level of the p86 component but slightly increased that of p70. Both replicative senescence and cellular quiescence decreased the activity of DNA-dependent protein kinase in WI-38 fibroblasts. On the other hand, SV-40 immortalization increased the activity of DNA-dependent protein kinase. The protein level of poly(ADP-ribose) polymerase (PARP) was strongly decreased in replicatively senescent fibroblasts. Quiescence of early-passage fibroblasts also slightly reduced the protein level of PARP. Apoptosis was not observed in replicatively senescent fibroblasts. Our results show that replicative senescence and to some extent cellular quiescence down-regulate the recognition system of DNA damage involving Ku autoantigens, DNA-dependent protein kinase, and PARP and hence could enhance the accumulation of DNA damage during aging.

Amino Acid Sequence↗

PubMed2004

The p16INK4a-RB pathway: molecular link between cellular senescence and tumor suppression.

The p16INK4a tumor suppressor protein functions as an inhibitor of CDK4 and CDK6, the D-type cyclin-dependent kinases that initiate the phosphorylation of the retinoblastoma tumor suppressor protein, RB. Thus, p16INK4a has the capacity to arrest cells in the G1-phase of the cell cycle and its probable physiological role is in the implementation of irreversible growth arrest termed cellular senescence. Cellular senescence is a state of permanent growth arrest that can be induced by a variety of stresses such as DNA-damage and aberrant mitogenic signaling in human primary cells. In contrast to normal cells, the function of the p16INK4a gene or its downstream mediators is frequently deregulated in many types of human cancers, illustrating the importance of cellular senescence in tumor suppression. Here we discuss the molecular mechanisms that direct cellular senescence and reveal its potential for tumor suppression.

Cell Cycle↗

PubMed2005

Defining the domains of human polynucleotide phosphorylase (hPNPaseOLD-35) mediating cellular senescence.

To fully comprehend cellular senescence, identification of relevant genes involved in this process is mandatory. Human polynucleotide phosphorylase (hPNPase(OLD-35)), an evolutionarily conserved 3', 5' exoribonuclease mediating mRNA degradation, was first identified as a predominantly mitochondrial protein overexpressed during terminal differentiation and senescence. Overexpression of hPNPase(OLD-35) in human melanoma cells and melanocytes induces distinctive changes associated with senescence, potentially mediated by direct degradation of c-myc mRNA by this enzyme. hPNPase(OLD-35) contains two RNase PH (RPH) domains, one PNPase domain, and two RNA binding domains. Using deletion mutation analysis in combination with biochemical and molecular analyses we now demonstrate that the presence of either one of the two RPH domains conferred similar functional activity as the full-length protein, whereas a deletion mutant containing only the RNA binding domains was devoid of activity. Moreover, either one of the two RPH domains induced the morphological, biochemical, and gene expression changes associated with senescence, including degradation of c-myc mRNA. Subcellular distribution confirmed hPNPase(OLD-35) to be localized both in mitochondria and the cytoplasm. The present study elucidates how a predominantly mitochondrial protein, via its localization in both mitochondria and cytoplasm, is able to target a specific cytoplasmic mRNA, c-myc, for degradation and through this process induce cellular senescence.

Blotting, Northern↗

PubMed2002

Identification and cloning of human polynucleotide phosphorylase, hPNPase old-35, in the context of terminal differentiation and cellular senescence.

Terminal differentiation and cellular senescence display common properties including irreversible growth arrest. To define the molecular and ultimately the biochemical basis of the complex physiological changes associated with terminal differentiation and senescence, an overlapping-pathway screen was used to identify genes displaying coordinated expression as a consequence of both processes. This approach involved screening of a subtracted cDNA library prepared from human melanoma cells induced to terminally differentiate by treatment with fibroblast IFN and mezerein with mRNA derived from senescent human progeria cells. This strategy identified old-35, which encodes an evolutionary conserved gene, human polynucleotide phosphorylase (hPNPase(old-35)), that is regulated predominantly by type I IFNs. The hPNPase(OLD-35) protein localizes in the cytoplasm of human cells and induces RNA degradation in vitro, as does its purified bacterial protein homologue. Ectopic expression of hPNPase(old-35) in human melanoma cells reduces colony formation, confirming inhibitory activity of this RNA-degradation enzyme. Identification of hPNPase(old-35), an IFN-inducible 3'-5' RNA exonuclease, provides additional support for a relationship between IFN action and RNA processing and suggests an important role for this gene in growth control associated with terminal differentiation and cellular senescence.

Amino Acid Sequence↗

PubMed2003

Bleomycin induces cellular senescence in alveolar epithelial cells.

Cellular senescence is a state of irreversible growth arrest. In this paper the authors examined whether bleomycin, an agent that causes pulmonary fibrosis, induces the senescence of alveolar epithelial cells. Type II-like alveolar epithelial (A549) cells or rat primary type II cells were exposed to bleomycin and then evaluated for markers of cellular senescence. Bleomycin was also administered intratracheally in C57BL/6 mice. The authors found that exposure to bleomycin induced cellular senescence in A549 cells and rat primary type II cells. The senescence was characterised by a dose- and time-dependent increase in senescence-associated beta-galactosidase activity, senescence-associated changes in cell morphology, an increase in cell size and lysosomal mass, the overexpression of p21 protein, and irreversible growth arrest. The intratracheal injection of bleomycin in mice induced an increase in senescence-associated beta-galactosidase activity in type II epithelial cells, reaching a maximum at day 7. These results suggest that bleomycin induces a phenotype that is indistinguishable from that of senescence in alveolar epithelial cells. The induction of epithelial senescence by bleomycin may contribute to the pathway of impaired re-epithelialisation leading to pulmonary fibrosis.

Animals↗

PubMed2003

Role of IFI 16, a member of the interferon-inducible p200-protein family, in prostate epithelial cellular senescence.

Recent studies have implicated interferon signaling in the regulation of cellular senescence. However, the role of specific interferon-inducible proteins in cellular senescence remains to be defined. Here we report that IFI 16, an interferon-inducible transcriptional modulator from the p200-protein family, contributes to cellular senescence of prostate epithelial cells. Normal human prostate epithelial cells (PrEC) in culture expressed detectable levels of IFI 16, and the levels increased more than fourfold when cells approached cellular senescence. Consistent with a role of IFI 16 in cellular senescence, human prostate cancer cell lines either did not express IFI 16 or expressed a variant form, which was primarily detected in the cytoplasm of prostate cancer cells and not in the nucleus. Moreover, overexpression of functional IFI 16 in human prostate cancer cell lines inhibited colony formation. Additionally, ectopic expression of IFI 16 in clonal prostate cancer cell lines was associated with a senescence-like phenotype, production of senescence-associated beta-galactosidase (a biochemical marker for cellular senescence), and reduction of S-phase cells in culture. Importantly, upregulation of p21WAF1 and inhibition of E2F-stimulated transcription accompanied inhibition of cell growth by IFI 16 in prostate cancer cell lines. Collectively, our observations support the idea that increased levels of IFI 16 in PrECs contribute to senescence-associated irreversible cell growth arrest.

Adenocarcinoma↗

PubMed2006

Cellular senescence as a stress response.

PURPOSE: This review discusses cellular senescence, the state in which normal cells do not respond to growth stimuli, and shows characteristic alterations in their cytologic and biochemical properties and their gene expression profiles. METHODS AND RESULTS: Cellular senescence is elicited by various stresses. It was recently shown that the stress-induced mitogen-activated protein kinase p38 has a pivotal role in inducing cellular senescence. This finding provided biochemical evidence to support the notion that cellular senescence is a kind of stress response. CONCLUSION: Stress responses are typically found in cells and organisms surviving unfavorable environmental conditions. It can be argued that cellular senescence is an adaptive process that maintains the cell's viability by reducing the energy consumed for reproduction (ie, cell division) and differentiation-related activities.

Cellular Senescence↗

PubMed2006

Decreased expression of Bmi1 is closely associated with cellular senescence in small bile ducts in primary biliary cirrhosis.

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, the decreased bmi1 expression caused by oxidative stress may be involved in the pathogenesis of cellular senescence of biliary epithelial cells in primary biliary cirrhosis.

Animals↗

PubMed2004

Chromosome positional effects of gene expressions after cellular senescence.

Normal human fibroblasts stop dividing after a limited number of cell divisions termed cellular senescence. Telomere shortening has been shown to be the main factor that causes cellular senescence, however, the molecular mechanism of how telomere shortening causes cellular senescence is unclear. Here we analyze the relationship between gene expressions and their chromosomal locations during cellular senescence. It appears that the expression of genes located in chromosome 4 is preferentially altered after senescence. Moreover, we identify four chromosomal loci in which gene expressions are affected by senescence. Finally, we show that there is no preferential alteration of telomere-proximal genes during cellular senescence, implying that cellular senescence is not caused by derepression of telomere-proximal genes.

Cell Cycle↗

PubMed2005

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

Cellular senescence has been theorized to oppose neoplastic transformation triggered by activation of oncogenic pathways in vitro, 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 cancer. Although they are functionally distinct, reciprocal cooperation has been proposed, as PTEN is thought to regulate p53 stability, and p53 to enhance PTEN transcription. 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.

ADP-Ribosylation Factors↗

PubMed2003

Cellular senescence, an unpopular yet trustworthy tumor suppressor mechanism.

The term "cellular senescence" refers to the state in which normal cells irreversibly stop dividing. Historically, this condition was first inferred from the finding that normal human fibroblasts cease dividing after a limited number of cell divisions. Since then, cellular senescence has been discussed as a potential cause of aging of organisms. However, recent studies have significantly expanded our view of cellular senescence in terms of both mechanistics and biological significance. Accordingly, cellular senescence is now considered to play an important adaptive role, namely, a tumor suppressor function. This review will focus on recent findings that have contributed to the elucidation of the adaptive role of cellular senescence.

Animals↗

PubMed2006

A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation.

Cellular senescence is a stable state of proliferative arrest that provides a barrier to malignant transformation and contributes to the antitumor activity of certain chemotherapies. Senescent cells can accumulate senescence-associated heterochromatic foci (SAHFs), which may provide a chromatin buffer that prevents activation of proliferation-associated genes by mitogenic transcription factors. Surprisingly, we show that the High-Mobility Group A (HMGA) proteins, which can promote tumorigenesis, accumulate on the chromatin of senescent fibroblasts and are essential structural components of SAHFs. HMGA proteins cooperate with the p16(INK4a) tumor suppressor to promote SAHF formation and proliferative arrest and stabilize senescence by contributing to the repression of proliferation-associated genes. These antiproliferative activities are canceled by coexpression of the HDM2 and CDK4 oncogenes, which are often coamplified with HMGA2 in human cancers. Our results identify a component of the senescence machinery that contributes to heterochromatin formation and imply that HMGA proteins also act in tumor suppressor networks.

Animals↗

PubMed1990

Induction of cellular senescence in immortalized cells by human chromosome 1.

The control of cellular senescence by specific human chromosomes was examined in interspecies cell hybrids between diploid human fibroblasts and an immortal, Syrian hamster cell line. Most such hybrids exhibited a limited life span comparable to that of the human fibroblasts, indicating that cellular senescence is dominant in these hybrids. Karyotypic analyses of the hybrid clones that did not senesce revealed that all these clones had lost both copies of human chromosome 1, whereas all other human chromosomes were observed in at least some of the immortal hybrids. The application of selective pressure for retention of human chromosome 1 to the cell hybrids resulted in an increased percentage of hybrids that senesced. Further, the introduction of a single copy of human chromosome 1 to the hamster cells by microcell fusion caused typical signs of cellular senescence. Transfer of chromosome 11 had no effect on the growth of the cells. These findings indicate that human chromosome 1 may participate in the control of cellular senescence and further support a genetic basis for cellular senescence.

Animals↗

PubMed2004

Iron accumulation during cellular senescence.

Iron accumulates as a function of age and is associated with the pathology of numerous age-related diseases. These changes may be caused by altered iron homeostasis at the cellular level, yet this is poorly understood. Therefore, changes in iron content in primary human fibroblasts were studied in culture models of cellular senescence. Total iron content increased exponentially during cellular senescence, reaching approximately 10-fold higher levels than young cells. Increasing intracellular iron levels through iron-citrate supplementation or decreasing intracellular iron levels using iron-selective chelators had little effect on cellular life span and markers of cellular senescence when used at subtoxic doses. However, accelerating cellular senescence with low-dose H(2)O(2) also accelerated senescence-associated iron accumulation. Delaying cellular senescence with N-tert-butyl-hydroxylamine (NtBHA) attenuated senescence-associated iron accumulation. Furthermore, H(2)O(2) or NtBHA had no effect on iron intracellular levels in immortalized fibroblasts. Thus, iron accumulation is not a cause, but a consequence of normal cellular senescence in vitro. Senescence-associated iron accumulation may contribute to the increased oxidative stress and cellular dysfunction seen in senescent cells.

Aging↗

PubMed2006

Cellular senescence and DNA repair.

Aging is a complex process that results in functional decline and mortality of the organisms. On the cellular lever, cellular senescence has been used as a model for aging. Therefore, understanding cellular senescence has important health implications. Initial observations suggest that cellular senescence is the result of telomere shortening. Recent findings suggest that cellular senescence could be triggered by DNA damage. In fact, both telomere shortening and DNA-damage-induced cellular senescence share a common mechanism, the DNA damage response pathway. This review will discuss the link between DNA repair defects and cellular senescence.

Aging↗

PubMed1998

Mapping a novel cellular-senescence gene to human chromosome 2q37 by irradiation microcell-mediated chromosome transfer.

To identify the subchromosomal region that carries the cellular-senescence-restoring program of the human cervical carcinoma cell line SiHa, we constructed by irradiation microcell-mediated chromosome transfer a library of mouse A9 cells containing various fragments of human chromosome 2 tagged with pSV2neo in 2p11-p12. Eighty-seven clones were isolated and screened for the presence of human sequences by inter-Alu and inter-L1 polymerase chain reaction (PCR), and six clones exhibiting PCR-laddering patterns that differed from those of the A9 cells containing an intact chromosome 2 were examined further. Chromosome analysis and fluorescence in situ hybridization (FISH) using human-specific repetitive sequences revealed that four of these clones contained single subchromosomal transferable fragments (STFs). Southern blot hybridization of 14 cosmid markers revealed that the STFs in A9 cells were derived from human chromosome 2. These STFs were transferred into SiHa cells by microcell fusion, and one of the STFs restored the cellular-senescence program. The concordance of the cellular-senescence-restoring program with the presence or absence of specific DNA fragments of chromosome 2 indicated that the putative cellular-senescence gene was located in 2q32-qter. For more detailed mapping, we constructed mouse A9 cells containing STFs derived from human chromosome 2 tagged with pSTneo at different regions in 2q31-qter. PCR-laddering and FISH analyses were used to identify six clones that contained different STFs. These STFs were transferred into SiHa cells, and one of the three clones that restored cellular senescence contained a small fragment of human chromosome 2. This STF was shown by PCR analysis using 14 human chromosome 2-specific primer pairs to be smaller than 12.2 cM and was mapped to the 2q37 region by FISH analysis with inter-Alu PCR. Beta-galactosidase activity, which is a biomarker of senescent cells, and telomerase activity similar to that found in parental SiHa cells were detected in SiHa microcell hybrids, suggesting that the putative cellular-senescence gene was not involved in a telomerase pathway but rather in an alternate pathway of cellular senescence.

Animals↗

PubMed2003

TGF-beta cytokines increase senescence-associated beta-galactosidase activity in human prostate basal cells by supporting differentiation processes, but not cellular senescence.

The family of transforming growth factors betas (TGF-betas) comprises molecules involved in growth inhibition, stress-induced premature senescence, epithelial mesenchymal transition and differentiation processes. The aim of this study was to clarify the effect of long term exposure of human prostate basal cells to TGF-betas, which are found in high concentrations in prostatic fluid and areas of benign prostatic hyperplasia (BPH). Basal cell cultures established from prostate explants (n=3) were either grown into cellular senescence, or stimulated with TGF-beta1, beta2 and beta3. Similar to cellular senescence, TGF-beta stimulation resulted in an increase of SA-beta galactosidase (SA-beta-gal) activity, flattened and enlarged cell morphology, and down-regulation of the inhibitor of differentiation Id-1. TGF-beta-treated prostate epithelial cells neither showed terminal growth arrest nor induction of important senescence-relevant genes, such as p16(INK4A), IFI-6-16, IGFBP-3 or Dkk-3. Cells stained positive for cytokeratins 8/18, but did not express other lumenal markers, such as prostate-specific antigen and androgen-receptors. TGF-betas increased also the expression of the mesenchymal marker vimentin, indicating that basal epithelial cells underwent differentiation with lumenal and mesenchymal features. In contrast, in vitro-differentiated neuroendocrine-like cells from prostate organoide cultures, expressing chromogranin A and cytokeratin 18, strongly stained positive for SA-beta-gal. Thus, SA-beta-gal activity is not only a marker for senescence, but also for differentiation of human prostate epithelial cells. With regard to the in vivo situation, in addition to cellular senescence, TGF-beta could contribute to the increased number of SA-beta-gal positive epithelial cells in BPH.

Aged↗