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Results for “Cellular Senescence”

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PubMed2005

Prolonged unbalanced growth induces cellular senescence markers linked with mechano transduction in normal and tumor cells.

Cellular senescence is induced by diverse means and hence thought to be mediated by multiple pathways. We show that prolonged unbalanced growth due to retardation of DNA replication elicits a senescence-like phenomenon irrespective of the cell type. In fact, modest inhibition of DNA replication by various means led to cell swelling, cytoskeletal alterations, and irregularly enlarged, flat cell shape. Such cells upregulated senescence-associated genes, and eventually lost division potential. These phenotypes, which define cellular senescence, were virtually reversed by reducing protein synthesis or blocking ERK of the MAP kinase family. These results suggest that cellular senescence is a manifestation of prolonged unbalanced growth linked with mechano transduction and can be prevented by at least two different ways.

Actins↗

PubMed1999

The effect of passage number on fibroblast cellular senescence in patients with chronic venous insufficiency with and without ulcer.

BACKGROUND: Fibroblasts (fb) cultured from venous ulcer patients and patients with venous reflux disease without ulcer demonstrate characteristics of cellular senescence, such as increased fibronectin level and senescence-associated beta-galactosidase (SA beta-gal) positive cells. Cellular senescence is an in vitro event characterized by the progressive loss of proliferative capacity with increased passage number, and has been associated with impaired healing in vivo. This report examines progressive stages of cellular senescence in fb from the distal area (du-fb) and proximal fb (pu-fb) of patients with venous ulcer, as well as in distal fb (dr-fb) and proximal fb (pr-fb) from patients with venous reflux without ulcer, by comparing the population doubling time (T) and percent SA beta-gal expression. RESULTS: The mean value of T over 6 passages for fb in the ulcer group was 132.5 +/- 29.0 hours for pu-fb and 492.9 +/- 146.2 hours for du-fb (P = 0.0009). For fb in the reflux group the mean value of T over 5 passages was 79.3 +/- 12.8 hours for pr-fb and 94.2 +/- 16.8 hours for dr-fb (P = 0.8). Comparing ulcer and reflux fb, no difference in T was observed between pu-fb and pr-fb (P = 0.6), but a difference was noted between du-fb and dr-fb (P = 0.0004). The mean percent SA beta-gal activity for fb in the ulcer group was 11.2% +/- 3.1% for pu-fb and 63.8% +/- 8.9% for du-fb (P = 0.0001). Individual passages demonstrated significant difference (P <0.05) in SA beta-gal activity between pu-fb and du-fb at early and late passages. No difference was noted in SA beta-gal activity for fb in the reflux group or between pu-fb and pr-fb, but comparison between du-fb and dr-fb was significant (63.8% +/- 8.9% versus 7.8% +/- 2.9%; P = 0.0001). CONCLUSIONS: The in vitro passage of du-fb and pu-fb in chronic venous ulcer patients has an effect on T and cellular senescence as measured by SA beta-gal activity. Our data further suggest that du-fb are at a more progressive stage of cellular senescence when compared with pu-fb, and more importantly with fb cultured from patients with venous reflux without ulcer. These findings are consistent with impaired wound healing of venous stasis ulcer. The accumulation of senescent fb and a more advanced stage of cellular senescence of du-fb may explain why repeated episodes of venous ulceration are resistant to conservative treatment and require more aggressive measures of therapy.

Adult↗

PubMed2005

p63 deficiency activates a program of cellular senescence and leads to accelerated aging.

The p53 tumor suppressor plays a key role in organismal aging. A cellular mechanism postulated to drive the aging process is cellular senescence, mediated in part by p53. Although senescent cells accumulate in elderly individuals, most studies have relied on correlating in vitro senescence assays with in vivo phenotypes of aging. Here, using two different mouse models in which the p53-related protein p63 is compromised, we demonstrate that cellular senescence and organismal aging are intimately linked and that these processes are mediated by p63 loss. We found that p63(+/-) mice have a shortened life span and display features of accelerated aging. Both germline and somatically induced p63 deficiency activates widespread cellular senescence with enhanced expression of senescent markers SA-beta-gal, PML, and p16(INK4a). Using an inducible tissue-specific p63 conditional model, we further show that p63 deficiency induces cellular senescence and causes accelerated aging phenotypes in the adult. Our results thus suggest a causative link between cellular senescence and aging in vivo, and demonstrate that p63 deficiency accelerates this process.

Aging↗

PubMed2006

Molecular basis for the cellular senescence program and its application to anticancer therapy.

Although dysfunctional telomeres and oncogenic or stressful stimuli are known to trigger cellular senescence in normal human diploid cells, the molecules and signaling network involved in the cellular senescence program are not fully understood. We have been trying to identify cellular senescence-inducing factors by various means. First, we screened for an extrinsic signal that can induce cellular senescence in human lung adenocarcinoma cell line A549, and identified transforming growth factor-beta (TGF-beta) as the cellular senescence-inducing factor. Cancer cells senesced by treatment with TGF-beta impaired tumorigenicity both in vitro and in vivo, suggesting that cellular senescence functions as a tumor suppression mechanism. Next, we identified 86 independent senescence-associated genes by subtractive screening using A549-derived cell lines. Thirdly, we established novel cell lines (AST cells) from A549 cells exposed to mild oxidative stress. AST cells demonstrated functional impairment of telomerase due to perturbed subcellular localization of human telomerase reverse transcriptase, suggesting that mild oxidative stress might affect the cell fate of cancer cells. These results should provide insight into the molecular basis of the cellular senescence program.

Cellular Senescence↗

PubMed1992

Cellular senescence.

The ageing of cells, cellular senescence, is an event that is encountered in all normal cells. Cells grown in vitro have a limited life span and do not grow well after a certain number of divisions. They cease to divide and eventually die. In accordance with this, the life expectancy of an established cell culture depends on the age of the donor. Cells that have undergone immortalization via a crisis period of transformation by chemicals or viruses, as well as malignant cell lines in general, have an ability to divide indefinitely. A distinct form of cell death, apoptosis or programmed cell death, is encountered in many physiological situations like in keratinocyte differentiation.

Animals↗

PubMed1993

Genetic and molecular basis for cellular senescence.

Normal human and rodent cells in culture exhibit a finite life span at the end of which they exhibit morphological changes and cease proliferating, a process termed cellular senescence or cellular aging. Many cancer cells differ from normal cells in that they do not senesce and have an indefinite life span in culture, suggesting that alterations relating to cellular senescence are involved in the neoplastic evolution of tumor cells. Recent experimental results strongly support a genetic basis for cellular senescence. Defects in the senescence program in transformed cells can be corrected by introduction of a specific chromosome from normal cells into the abnormal cells. Using this approach, possible senescence genes have been mapped to specific chromosomes. Cell cycle control genes that regulate entry into the DNA synthetic phase of the cell cycle must be altered in senescent cells. Recent findings suggest that phosphorylation of the retinoblastoma gene is altered in senescent cells. It is possible, but not yet proven, that aging at the cellular level contributes to the aging of the individual. Therefore, an understanding of cellular senescence at the genetic and molecular levels may provide new insights into both the cancer and aging processes.

Animals↗

PubMed2006

Cellular senescence, cancer, and organismal aging: a paradigm shift.

Cellular senescence is an anti-cancer mechanism and may contribute to organismal aging. A change in paradigm has been proposed that cellular senescence may reduce cancer mortality rather than promote it late in life, and thus positively contributes to longevity in organisms with renewable tissues as a common mechanism across the species.

Aging↗

PubMed1997

Multiple pathways to cellular senescence: role of telomerase repressors.

Telomeres progressively shorten with age in somatic cells in culture and in vivo because DNA replication results in the loss of sequences at the 5' ends of double-stranded DNA. Whereas somatic cells do not express the enzyme, telomerase, which adds repeated telomere sequences to chromosome ends, telomerase activity is detected in immortalised and tumour cells in vitro and in primary tumour tissues. This represents an important difference between normal cells and cancer cells, suggesting that telomere shortening causes cellular senescence. Hybrids between immortal cells and normal cells senesce, indicating that immortal cells have lost, mutated or inactivated genes that are required for the programme of senescence in normal cells. Genes involved in the senescence programme have been mapped to over ten different genetic loci using microcell fusion to introduce human chromosomes and restore the senescence programme. Multiple pathways of cellular senescence have also been demonstrated by chromosome transfer, indicating that the functions of the mapped senescence genes are probably different. One possibility is that one or more of these senescence genes may suppress telomerase activity in immortal cells, resulting in telomere shortening and cellular senescence. To test this hypothesis, telomerase activity and the length of terminal restriction fragments (TRFs) have been examined in microcell hybrids. Re-introduction of a normal chromosome 3 into the renal cell carcinoma cell line RCC23, which has the short arm of chromosome 3, restored cellular senescence. The loss of indefinite growth potential was associated with the loss of telomerase activity and shortening of telomeres in the RCC cells containing the introduced chromosome 3. However, microcell hybrids that escaped from senescence and microcell hybrids with an introduced chromosome 7 or 11 maintained telomere lengths and telomerase activity similar to the parental RCC23. Thus, restoration of cellular senescence by chromosome 3 is associated with repression of telomerase function in RCC cells. This evidence suggests that telomerase suppression is one of several pathways involved in immortalisation.

Animals↗

PubMed2006

How does cellular senescence prevent cancer?

It is widely believed that cellular senescence is a tumor suppressor mechanism; however, it has not been understood why it is advantageous for organisms to retain mutant cells is a postmitotic state rather than simply eliminating them by apoptosis. It has recently been proposed that the primary role of cellular senescence is in mitotic compartments of fixed size in which spatial considerations dictate that a deleted cell is replaced by a neighboring cell. In these situations, rather than eliminating the neoplastic clone, deletion of mutant cells can paradoxically lead to their increased turnover. If mutant cells become senescent, then the compartment is instead progressively filled by senescent cells until the mutant clone is eliminated. Since most of the genetic alterations responsible for malignancy arise in stem cells, this mechanism may have particular relevance to the stem cell niche. In this article the implications of this hypothesis are examined in detail and related to experimental results. It is further proposed here that blockage of stem cell niches by senescent stem cells may account for some of the functional alterations observed in stem cell compartments at old age. Clearly, the existence of senescent stem cells is central to the proposed hypothesis, and although there is preliminary evidence for this assertion it has yet to be proven in vivo. An experimental strategy involving double labeling of stem cells with a nucleotide label is described that can address this question.

Animals↗

PubMed2006

Cooperation between p53 and p130(Rb2) in induction of cellular senescence.

To determine pathways cooperating with p53 in cellular senescence when the retinoblastoma protein (pRb)/p16INK4a pathway is defunct, we stably transfected the p16INK4a-negative C6 rat glioma cell line with a temperature-sensitive mutant p53. Activation of p53(Val-135) induces a switch in pocket protein expression from pRb and p107 to p130(Rb2) and stalls the cells in late G1, early S-phase at high levels of cyclin E. Maintenance of the arrest depends on the functions of p130(Rb2) repressing cyclin A. Inactivation of p53 in senescent cultures restores the pocket proteins to initial levels and initiates progression into S-phase, but the cells fail to resume proliferation, likely due to DNA damage becoming apparent in the arrest and activating apoptosis subsequent to the release from p53-dependent growth suppression. The data indicate that p53 can cooperate selectively with p130(Rb2) to induce cellular senescence, a pathway that may be relevant when the pRb/p16INK4a pathway is defunct.

Animals↗

PubMed2005

Frequent cellular senescence in small bile ducts in primary biliary cirrhosis: a possible role in bile duct loss.

The pathogenesis of progressive bile duct loss in primary biliary cirrhosis remains unclear. In this study, the involvement of cellular senescence of biliary epithelial cells was examined in liver tissue samples from patients with primary biliary cirrhosis (n = 33), and compared with control diseased and normal livers (n = 83). In addition, cellular senescence was induced by oxidative stress in cultured mouse biliary epithelial cells. Biliary epithelial cells in small bile ducts in primary biliary cirrhosis, especially those in patients presenting with chronic non-suppurative cholangitis, frequently expressed senescence-associated beta-galactosidase, and senescence-associated p16(INK4) and p21(WAF1/CIP). In contrast, senescence-associated markers were rarely expressed in small bile ducts in control livers. The infiltration of myeloperoxidase-positive inflammatory cells into biliary epithelial cell layers was closely associated with the cellular senescence of biliary epithelial cells in early-stage PBC. Cellular senescence of cultured mouse biliary epithelial cells was induced by treatment with H2O2 via the p38MAPK-dependent pathway and nitric oxide-augmented H2O2-induced cellular senescence. Oxidative stress- and nitric oxide-mediated cellular senescence may be involved in bile duct lesions, which are followed by progressive bile duct loss in primary biliary cirrhosis.

Animals↗

PubMed2004

Cellular senescence induced loss of stem cell proportion in the skin in vitro.

BACKGROUND: It is known that cellular senescence could affect culture results. A previous study on K19 found that the loss of stem cell proportion is the reason for difficulties experienced when culturing aged keratinocytes. But the situation is unclear, because K19 is not generally accepted as an epidermal stem cell marker. OBJECTIVE: The aim of this study was to investigate the effects of cellular senescence caused by chronological aging or by repeated subcultures. METHODS: The effects of cellular senescence were investigated using monolayer cultures of keratinocytes and reconstructed epidermis. We prepared keratinocytes from donors of different ages and by repeated subcultures. Flow cytometric analysis was performed using alpha6 integrin and CD71 antibodies, and candidate keratinocyte stem cell proportions were separated according to reactivities to these antibodies. Living skin equivalents (LSEs) were reconstructed using keratinocytes from child, adult and elderly donors. RESULTS: Flow cytometric analysis showed a decrease in the candidate stem cell proportion in an age- or culture passage-dependent manner. LSE experiments showed that a reconstructed epidermis using child's keratinocytes was well formed compared to epidermis reconstructed using an elderly donor's keratinocytes. Different expression of proliferation markers was also observed according to donor age. CONCLUSION: Our results showed that cellular senescence by chronological aging or repeated sub-culture induced the loss of candidate stem cell proportion in keratinocyte cultures. This seems to be the reason why it is difficult to culture keratinocytes from the elderly or by repeatedly culturing keratinocytes in vitro.

Adult↗

PubMed1987

Cellular senescence revisited: a review.

The field of cellular senescence (cytogerontology) is reviewed. The historical precedence for investigation in this field is summarized, and placed in the context of more recent studies of the regulation of cellular proliferation and differentiation. The now-classical embryonic lung fibroblast model is compared to models utilizing other cell types as well as cells from donors of different ages and phenotypes. Modulation of cellular senescence by growth factors, hormones, and genetic manipulation is contrasted, but newer studies in oncogene involvement are omitted. A current consensus would include the view that the life span of normal diploid cells in culture is limited, is under genetic control, and is capable of being modified. Finally, embryonic cells aging in vitro share certain characteristics with early passage cells derived from donors of increasing age.

Aging↗

PubMed2006

E2F-1 is a critical modulator of cellular senescence in human cancer.

Senescence limits cellular proliferation, and therefore might be a mechanism which could suppress the progression of cancer. Herein we show that E2F1, a transcription factor essential to a cell cycle progress and a main target of tumor suppressor Rb, is a critical barrier for the induction of senescence. Human cancer cells transfected with siE2F1 were shown to express replicative senescence markers, in addition to yielding positive results upon SA-beta-Gal staining. Consistent with the notion of the critical role in senescence of E2F1, cells which overexpressed E2F1 proved to be immune to the induction of senescence. Importantly, it appears that E2F1 depletion-induced cancer cell senescence is not reliant on the integrity of either Rb or p53. Our results provide a molecular explanation for the selectivity with which senescence induction occurs, and also provides insights into the possibility of using E2F1 as a therapeutic target in the treatment of cancer.

Antibiotics, Antineoplastic↗

PubMed2003

Telomere shortening and cellular senescence in a model of chronic renal allograft rejection.

Cellular senescence has been suggested to play a role in the deterioration of renal graft function and has been linked to telomere shortening. We have investigated markers of cellular senescence in the F344 to LEW rat model of chronic renal transplant rejection. Syngeneic and LEW to F344 transplants were used as controls. Substantial telomere shortening was observed in all transplants, including allogeneic and syngeneic grafts from day 7 post-transplant onwards. Ischemia of native F344 kidneys was already sufficient to induce telomere shortening. It is known that shortened telomeres can activate cell cycle regulators, such as p21 and p16. Accordingly, all cases showed a transient p21 increase, with a maximum at day 7 and a sustained expression of p16. Importantly, senescence-associated beta-galactosidase staining, a cytological marker for senescence, was only observed in tubular epithelial cells of chronically rejecting F344 allografts from day 30 post-transplantation onwards. Long-term surviving LEW allografts or syngeneic F344 grafts were negative for senescence-associated beta-galactosidase. In conclusion, ischemia during transplantation results in telomere shortening and subsequent activation of p21 and p16, whereas senescence-associated beta-galactosidase staining is only present in chronically rejecting kidney grafts.

Animals↗

PubMed2005

Human papillomavirus oncoprotein E7 targets the promyelocytic leukemia protein and circumvents cellular senescence via the Rb and p53 tumor suppressor pathways.

Cellular senescence can be triggered by a variety of signals, including loss of telomeric integrity or intense oncogenic signaling, and is considered a potent, natural tumor suppressor mechanism. Previously, it was shown that the promyelocytic leukemia protein (PML) induces cellular senescence when overexpressed in primary human fibroblasts. The mechanism by which the PML IV isoform elicits this irreversible growth arrest is believed to involve activation of the tumor suppressor pathways p21/p53 and p16/Rb; however, a requirement for either pathway has not been demonstrated unequivocally. To investigate the individual contributions of p53 and Rb to PML-induced senescence, we used oncoproteins E6 and E7 from human papillomaviruses (HPVs), which predominantly target p53 and Rb. We show that E7, but not E6, circumvents PML-induced senescence. Using different E7 mutant proteins, dominant negative cyclin-dependent kinase 4, and p16 RNA interference, we demonstrate that Rb-related and Rb-independent mechanisms of E7 are necessary for subversion of PML-induced senescence and we identify PML as a novel target for E7. Interaction between E7 and a functional prosenescence complex composed of PML, p53, and CBP perturbs transcriptional activation of p53, thus highlighting a significant effect also on the p53 tumor suppressor pathway. Given the importance of HPV in the pathogenesis of cervical cancer, our results warrant a more detailed analyses of PML in HPV infections.

Acetylation↗

PubMed2001

Cellular senescence as a tumor-protection mechanism: the essential role of counting.

The term 'cellular senescence' has often been applied indiscriminately to any form of growth arrest of cultured cells that occurs either after some period in culture or following insults such as the overexpression of oncogenes. Recent reports have suggested there may be many mechanisms of cellular senescence. Our increasing understanding of the role of telomere shortening in the replicative aging of cultured fibroblasts now permits a re-examination of what may reasonably be called cellular senescence, and what most likely represents artifacts of the culture environment and/or specific cell-cycle control mechanisms.

Animals↗

PubMed1995

[Aging and cellular senescence].

Mechanisms of aging involve genetic programs and error accumulation. Cellular aging is an aspect of organismal aging from a point of view of age-dependent declines of tissue cells during the postreproductive aging process and a parallelism between enhanced individual and cellular aging in some genetic progeroid syndromes. Cellular senescence involves the gene-directed inhibition of replicative potential of cells. Cell fusion analysis has indicated that senescent normal and presenescent Werner syndrome cells cause the dominant suppression of DNA synthesis in the partner of either actively growing cells or any cells of the four complementation groups of immortalized human cells. Membrane proteins produced in senescent cells showed the biphasic DNA synthesis-inhibiting activity when assayed for young cells. Senescent cells showed the strong transcriptional repressions of early serum responsive genes (c-fos, c-jun, c-myc), late responsive genes of transcription factor E2F1 and cyclin E. In addition, the protein levels of CDK2 and cyclin E are also extremely low, with an increased level of the p53-dependent p21 Cip 1 protein which inhibits the kinase activity of cyclins/CDKs by forming complexes. Such characteristic molecular factors and mechanisms feature irreversible G1-arrest in cellular senescence.

Aging↗