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Results for “Cellular Senescence”

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PubMed1995

Time, telomeres and tumours: is cellular senescence more than an anticancer mechanism?

Normal diploid cells, by definition, have a limited life span: they senesce after a set number of divisions both in vivo and in culture. It has been hypothesized that the molecular mechanism that measures the life span of a cell probably involves the shortening of telomeres that occurs with each round of DNA replication. This loss of telomeres is thought to induce antiproliferative signals that result in the induction of cellular senescence. In this article, Woodring Wright and Jerry Shay present a hypothesis for the mechanisms by which telomere shortening regulates cellular physiology and argue that cellular senescence is not only an anticancer mechanism but is also the cause of many of the degenerative changes of aging.

Journal Article↗

PubMed2001

Clusterin/apolipoprotein J is a novel biomarker of cellular senescence that does not affect the proliferative capacity of human diploid fibroblasts.

Normal human fibroblasts have a limited replicative potential in culture and eventually reach a state of irreversible growth arrest, termed senescence. In a previous study aiming to identify genes that are differentially regulated during cellular senescence we have cloned clusterin/apolipoprotein J (Apo J), a 80 kDa secreted glycoprotein. In the current report we pursue our studies and show that senescence of human diploid fibroblasts is accompanied by up-regulation of both Apo J mRNA and protein levels, but with no altered biogenesis, binding partner profile or intracellular distribution of the two Apo J forms detected. To analyze the causal relationship between senescence and Apo J protein accumulation, we stably overexpressed the Apo J gene in primary as well as in SV40 T antigen-immortalized human fibroblasts and we showed no alteration of the proliferative capacity of the transduced cells. Despite previous reports on tumor-derived cell lines, overexpression of Apo J in human fibroblasts did not provide protection against apoptosis or growth arrest induced by hydrogen peroxide. Overall, our results suggest that Apo J overexpression does not induce senescence but it is rather a secondary consequence of the senescence phenotype. To our knowledge this is the first report that provides a functional analysis of human Apo J during replicative senescence.

Antigens, Differentiation↗

PubMed1968

Cellular senescence, radiation damage to mitochondria, and the compensatory response in ripening pear fruits.

A compensatory response, viz. in vivo recovery from radiation damage to mitochondria, occurs in preclimacteric pear fruits (Pyrus communis L.) treated with ionizing radiation. The compensatory response is absent or markedly impaired in senescent fruits irradiated at or near the climacteric peak. Senescent cells failed to recover from harmful effects of radiation on: 1) mitochondrial yield, 2) in vivo incorporation of amino acids into mitochondrial protein, and 3) mitochondrial respiratory control and ADP/O. A diminished response to "split-dose" irradiation and a delayed rate of recovery confirmed the degeneracy and loss of compensatory power with cell age.A loss of restorative activity, especially in mitochondria that supply the cell with essential energy, may underlie the more obvious signs of cumulative stress that accompany cellular senescence. Use of ionizing radiation as an investigative tool and the molecular implications of radiation damage, recovery, and cellular senescence are discussed.

Journal Article↗

PubMed2000

Tumor suppressors and oncogenes in cellular senescence.

Cyclin-dependent kinase inhibitors p16(INK4a), p21(Cip1), and p27(Kip1) are regarded as key effectors of cellular senescence. In this review, we describe three senescence-inducing pathways involving these inhibitors, namely, the p16(INK4a)/Rb pathway, the p19(ARF)/p53/p21(Cip1) pathway, and the PTEN/p27(Kip1) pathway. We emphasize the participation of tumor suppressors and oncogenes in the regulation of these senescence-inducing pathways. Finally, we discuss the impact of the Ras and Myc oncogenes on the above-mentioned pathways.

Animals↗

PubMed1992

Changes in the migratory ability of human lung and skin fibroblasts during in vitro aging and in vivo cellular senescence.

The migration of human lung and skin fibroblasts was determined during in vitro aging and in vivo cellular senescence by measuring their migration from the edge of a denuded area of a monolayer. The migration of human fetal lung fibroblasts (TIG-1 and TIG-3) decreased only very slightly with increasing passage, whereas the migration of human fetal skin fibroblasts (TIG-3S) declined gradually: the difference in cell migratory ability between early and late passages was significant (P less than 0.05). The migratory patterns of skin fibroblasts from adult and elderly donors were also similar to that of fetal skin fibroblasts. Next, the migratory abilities of fibroblast lines from adult and elderly donor groups were compared, using relatively early passaged cells. The migratory ability of the elderly-donor skin fibroblast lines was significantly lower (P less than 0.05) than that of the adult-donor skin fibroblast lines. Addition of suramin and monensin suppressed the migration of fibroblasts from fetal, adult and elderly donors, which implies that fibroblast migration is regulated by growth factors and matrix substances. The relationships between the age-dependent decline of migratory ability, growth factors and the extracellular matrix are discussed.

Adult↗

PubMed1995

Effect of cellular senescence and retinoic acid on the expression of cellular retinoic acid binding proteins in skin fibroblasts.

Retinoic acid (RA) has significant effects on a variety of cellular processes, including growth and differentiation. Retinoic acid has also been implicated as a major morphogen during embryogenesis. In the skin, both the epidermis and the dermis are extremely responsive to the effects of retinoids; however, the molecular mechanisms through which retinoids act in this tissue remain poorly understood. Two classes of proteins play roles in mediating the biological effects of retinoic acid. The nuclear receptors for retinoic acid are of two types, the initially described RARs, and the RXRs. Each of these nuclear receptor families has multiple isoforms and can function as a ligand-inducible transcription enhancing factor. A second class of receptor proteins exists for retinoic acid that are found in the cytoplasm, the cellular retinoic acid binding proteins (CRABPs). These proteins play a role in the binding, transport, and metabolism of retinoic acid. In previous studies, we have demonstrated that retinoic acid induces the expression of RAR beta and RAR gamma in human dermal fibroblasts. Moreover, we have also shown the selective transcriptional up-regulation of the RAR beta 2 isoform in senescent dermal fibroblasts and senescent human mammary epithelial cells. In order to further define molecules important in regulating the response of senescent dermal fibroblasts to retinoids, we demonstrate here that retinoic acid induces CRABP-II messenger RNA in human dermal fibroblasts in a dose-dependent manner. Moreover, we show that the induction by RA can be inhibited by actinomycin D, suggesting that the up-regulation may be mediated by a transcriptional mechanism. We further demonstrate that cycloheximide also has an effect on the up-regulation, suggesting a role for protein synthesis in the regulation of CRABP-II gene expression. We show that CRABP-II is a very stable messenger RNA species, in contrast to the mRNAs for RAR alpha, RAR beta, and RAR gamma. Of interest, we demonstrate no significant difference in the expression of CRABP-II between presenescent and senescent fibroblasts. Taken together, these data suggest that retinoic acid plays a central role in the regulation of CRABP-II gene expression in the dermal fibroblast and that this molecule is the major mediator of the cytoplasmic effects of retinoids in dermal fibroblasts. However, in contrast to RAR beta 2, there is no apparent change in the regulation of CRABP-II in senescent dermal fibroblasts.

Cellular Senescence↗

PubMed2000

Cytoplasmic retention of p-Erk1/2 and nuclear accumulation of actin proteins during cellular senescence in human diploid fibroblasts.

In order to investigate the role of signal transduction and the related changes of actin cytoskeleton organization in the process of cellular senescence, H-ras double mutants--V12S35, V12G37 and V12C40--proteins were expressed constitutively in human diploid fibroblast (HDF) cells by retrovirus infection at PD26. Constitutive expression of V12S35, V12G37 and V12C40 proteins induced premature senescence at PD38, PD47 and PD50, respectively, in contrast to the control cells at PD59. Premature senescence was evidenced by the slow cellular growth rate and SA-beta-galactosidase expression accompanied by morphological changes such as flat and large cell shape. Senescent HDF cells as well as the H-ras mutant expressers accumulated p-Erk1/2 in the cytoplasm with increased MEK activity and failed to translocate it to nuclei on EGF stimulation. Senescent HDF cells as well as V12S35 and V12G37 expressers were unable to export actin fibers from nucleus to cytoplasm, form stress fibers through the MAPK and Ral.GDS pathways. Perinuclear expression of Racl was prominent in the HDF cells and V12C40 expresser, while translocation of Racl from perinucleus to nucleus and strong expression of RhoA were observed in the V12S35 expresser. In summary, the induced premature senescence by H-ras double mutants were accompanied by nuclear accumulation of actin and Racl proteins, cytoplasmic retention of p-Erk1/2 and marked induction of RhoA expression mainly through dysregulation of the MEK pathway.

Actins↗

PubMedDate not supplied

Molecular genetic studies of cellular senescence.

The limited doubling potential of normal cells in culture was first proposed as a model for cellular aging by Hayflick in 1961. This phenomenon of in vitro cellular senescence is now well documented for a number of different normal human cell types. In an attempt to determine whether random events or programmed genetic processes were responsible for cellular aging, we performed a series of cell fusion studies. We determined that hybrids from fusion of normal with immortal human cells had limited proliferative potential, indicating that senescence is a dominant phenotype. We exploited the fact that immortality was recessive to assign a large number of different immortal human cell lines to four complementation groups for indefinite division. More recently, we have determined that the introduction of a single normal human chromosome 4 into HeLa (cervical carcinoma) cells by microcell fusion induced senescence in this immortal line. The results of these whole cell and microcell fusion studies support the hypotheses that propose senescence results from active, genetic mechanisms.

Cell Division↗

PubMed1994

Evidence for multiple pathways to cellular senescence.

Normal cells in culture generally senesce whereas tumor-derived cells are often, but not without exception, immortal and grow indefinitely. For cells to escape the senescence program, normal genes must be lost or inactivated as shown by somatic cell genetic studies. For example, the introduction of specific chromosomes by microcell-mediated chromosome transfer has been shown to induce senescence of human and rodent tumor cell lines, and the mapping of over ten senescence genes has been achieved by this method. In this study, we observed that two different normal chromosomes induce senescence in the same human endometrial carcinoma cell line, which suggests that multiple pathways to senescence are inactivated in this cell line. This hypothesis has implications for the mechanisms of cellular senescence and its role in carcinogenesis. Furthermore, this hypothesis can explain why not all tumor-derived cells are immortal.

Animals↗

PubMed2001

Cellular senescence as a tumor-suppressor mechanism.

Organisms with renewable tissues had to evolve mechanisms to prevent the development of cancer. One such mechanism is cellular senescence, which irreversibly arrests the growth of cells at risk for neoplastic transformation. Recent findings have revealed the complexities of the senescence phenotype and unexpected possible consequences for the organism.

Animals↗

PubMed1995

Normal human chromosome 2 induces cellular senescence in the human cervical carcinoma cell line SiHa.

For identification of the chromosome carrying cellular senescence-inducing activity, normal human chromosome 2, 3, 6, 7, 9, 11, or 12 tagged with a selectable marker gene (neo) was introduced into the human cervical carcinoma cell line SiHa via microcell-mediated chromosome transfer. Seventy-six percent (158/207) of the G418-resistant clones obtained by the transfer of chromosome 2 showed a remarkable change in morphology (cells were flat), and 93% (147/158) of them ceased to divide (senesced) prior to 6-9 population doublings, whereas most of the clones generated by the transfer of other chromosomes exhibited a morphology similar to that of the parental cells and continued to grow. Chromosome analyses suggested that cells which escaped from senescence contained only a small fragment derived from the transferred chromosome 2, whereas the transferred chromosomes were apparently intact in most of the continuously growing microcell hybrids with introduction of other chromosomes. These results indicate that the normal human chromosome 2 carries a gene or genes that induce cellular senescence in SiHa cells.

Animals↗

PubMed2006

Control of cellular senescence by CPEB.

Cytoplasmic polyadenylation element-binding protein (CPEB) is a sequence-specific RNA-binding protein that promotes polyadenylation-induced translation. While a CPEB knockout (KO) mouse is sterile but overtly normal, embryo fibroblasts derived from this mouse (MEFs) do not enter senescence in culture as do wild-type MEFs, but instead are immortal. Exogenous CPEB restores senescence in the KO MEFs and also induces precocious senescence in wild-type MEFs. CPEB cannot stimulate senescence in MEFs lacking the tumor suppressors p53, p19ARF, or p16(INK4A); however, the mRNAs encoding these proteins are unlikely targets of CPEB since their expression is the same in wild-type and KO MEFs. Conversely, Ras cannot induce senescence in MEFs lacking CPEB, suggesting that it may lie upstream of CPEB. One target of CPEB regulation is myc mRNA, whose unregulated translation in the KO MEFs may cause them to bypass senescence. Thus, CPEB appears to act as a translational repressor protein to control myc translation and resulting cellular senescence.

Animals↗

PubMed2005

The role of microglial cellular senescence in the aging and Alzheimer diseased brain.

With each cell division, telomeres progressively shorten until they reach a critical length, at which point the cells enter cellular senescence. Microglia, a non-neuronal cell type residing within the central nervous system (CNS), play vital roles in maintaining neuronal function, health, and survival in both the normal and pathological CNS. A recent article described an increased incidence of microglial cytoplasmic structural abnormalities (i.e., swelling, twisted and shortened processes, and fragmentation) and dystrophy occurring in the cerebral cortex of human brains with age. These results suggest that microglial dystrophy may be a result of, or contribute to, their senescence, which in turn may impair their neuron-sustaining functions and ultimately lead to neuronal cell death.

Aging↗

PubMed2004

Cellular senescence induced by p53-ras cooperation is independent of p21waf1 in murine embryo fibroblasts.

Oncogenic activation in primary murine fibroblasts initiates a senescence-like cell cycle arrest that depends on the p53 tumor suppressor pathway. Conditional p53 activation efficiently induced a reversible cell cycle arrest but was unable to induce features of senescence. In contrast, coexpression of oncogenic ras with p53 produced an irreversible cell cycle arrest that displayed features of cellular senescence. Introduction of a conditional murine p53 allele (p53val135) into double p53/p21-null mouse embryonic fibroblasts showed that p21waf1 was not required for this effect, since p53-/-;p21-/- double-null cells undergo terminal growth arrest with features of senescence following coexpression of oncogenic Ras and p53. Our results indicate that oncogenic activation of the Ras pathway in murine fibroblasts converts p53 into a senescence inducer through a p21waf1-independent mechanism.

Animals↗

PubMed2005

Telomere-independent cellular senescence in human fetal cardiomyocytes.

Fetal cardiomyocytes have been proposed as a potential source of cell-based therapy for heart failure. This study examined cellular senescence in cultured human fetal ventricular cardiomyocytes (HFCs). HFCs were isolated and identified by immunocytochemistry and RT-PCR. Cells were found to senesce after 20-25 population doublings, as determined by growth arrest, morphological changes and senescence-associated beta-galactosidase activity. Using the telomeric repeat amplification protocol assay, telomerase activity was undetectable in primary HFCs. Cells were transduced to express the human reverse transcriptase subunit (hTERT) of telomerase. This resulted in greatly increased telomerase activity, but no significant lifespan extension. Analysis of telomere length in primary HFCs revealed that the senescent phenotype was not accompanied by telomere shortening. Telomeres in hTERT-positive cells were elongated in comparison with primary cells, and elongation was retained in senescent cells. Levels of the tumor suppressor protein p16INK4A increased in all senescent cells whether telomerase-positive or -negative. Senescence was accompanied by a decline in transcript levels of the polycomb gene Bmi-1, Ets1 and Ets2 transcription factors, and Id1, Id2 and Id3 helix-loop-helix proteins, suggesting roles for these genes in maintenance of cardiomyocyte proliferative capacity. In addition to offering novel insights into the behavior of human fetal cardiomyocytes in culture, these findings have implications for the development of a cell-based therapy for cardiac injury using primary fetal heart tissue.

Cell Hypoxia↗

PubMed1997

Regulatory mechanisms of replication growth limits in cellular senescence.

Normal human diploid fibroblasts cannot divide indefinitely in culture. At the end of their lifespan they withdraw from the cell cycle permanently by a process termed cellular senescence. Recent molecular studies indicate that upregulation of two inhibitors of cyclin-dependent kinases, p16 and p21, is responsible for blocking the G1/S transition in senescent cells. Although the state of senescence resembles terminal differentiation in that both exhibit irreversible growth arrest and resistance to apoptosis, other molecular changes are seen only in senescent cells. This suggests that the signal pathway specific for senescence is present in normal cells. Changes in chromosomes, such as progressive shortening of the telomeres and erosive damage by detrimental by-products in metabolism, may be the signals that trigger senescence, leading to the inactivation of cell cycle progression. On the other hand, it seems that a dominant genetic program is intrinsically preset to ensure a growth limit in the normal cell. This notion is supported by cell fusion and microcell transfer experiments which show that escaping from senescence requires recessive mutations in senescence-specific genes. Identification of these participating genes and clarification of their mode of action will provide the basis for understanding the mechanisms governing the differences between mortality in normal cells and immortality in cancer cells.

Animals↗

PubMed2006

Death-associated protein 3 regulates cellular senescence through oxidative stress response.

Death-associated protein 3 (DAP3) has been originally identified as a positive mediator of apoptosis. It has been revealed recently that the predominant localization of DAP3 to mitochondria implies its functional involvement in mitochondrial metabolism in addition to apoptosis. However, little is known about the molecular basis of these physiological functions of DAP3. Here, we demonstrate that DAP3 is reduced in both replicative and premature senescence induced by oxidative stress, and the DAP3 reduction induced by oxidative stress is observed mostly in a mitochondrial fraction. Using DAP3-specific short hairpin RNA (shRNA) in a clonogenic survival assay, we reveal that reduction of DAP3 induces resistance to oxidative stress and decreases intracellular reactive oxygen species (ROS) production. Furthermore, this strategy allows us to show that loss of DAP3 is involved in the avoidance of replicative senescence in mouse embryonic fibroblasts (MEFs). Thus, our study offers an insight into the potential regulatory function of mitochondrial DAP3 involved in cellular senescence.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence.

The p16(INK4a) cyclin-dependent kinase inhibitor has a key role in establishing stable G1 cell-cycle arrest through activating the retinoblastoma (Rb) tumour suppressor protein pRb in cellular senescence. Here, we show that the p16(INK4a) /Rb-pathway also cooperates with mitogenic signals to induce elevated intracellular levels of reactive oxygen species (ROS), thereby activating protein kinase Cdelta (PKCdelta) in human senescent cells. Importantly, once activated by ROS, PKCdelta promotes further generation of ROS, thus establishing a positive feedback loop to sustain ROS-PKCdelta signalling. Sustained activation of ROS-PKCdelta signalling irreversibly blocks cytokinesis, at least partly through reducing the level of WARTS (also known as LATS1), a mitotic exit network (MEN) kinase required for cytokinesis, in human senescent cells. This irreversible cytokinetic block is likely to act as a second barrier to cellular immortalization ensuring stable cell-cycle arrest in human senescent cells. These results uncover an unexpected role for the p16(INK4a)-Rb pathway and provide a new insight into how senescent cell-cycle arrest is enforced in human cells.

Acetophenones↗