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At least 19 recordsLinked to original sources

PubMed1998

Differential expression of senescence-associated mRNAs during leaf senescence induced by different senescence-inducing factors in Arabidopsis.

Four cDNA clones, named pSEN2, pSEN3, pSEN4, and pSEN5, for mRNAs induced during leaf senescence in Arabidopsis thaliana were characterized. The clones were isolated from a cDNA library of detached leaves incubated in darkness for 2 days to accelerate senescence, first by differential screening and then by examining expression of the primarily screened clones during age-dependent leaf senescence. Transcript levels detected by these cDNA clones, thus, were up-regulated in an age-dependent manner and during dark-induced leaf senescence. In contrast, when leaf senescence was induced by ethylene, ABA or methyljasmonate, the transcript level detected by the clones was differentially regulated depending on the senescence-inducing hormones. The transcript level for pSEN4 increased during senescence induced by all three hormones, while the transcript detected by the pSEN2 clone did not increase during senescence induced by ethylene. The transcript level for pSEN5 was increased upon ABA-induced senescence but decreased during ethylene-induced senescence. The pSEN3 clone detected multiple transcripts that are differentially regulated by these factors. The results show that, although the apparent senescence symptoms of Arabidopsis leaf appear similar regardless of the senescence-inducing factors, the detailed molecular state of leaf cells during senescence induced by different senescence-inducing factors is different. The pSEN3 clone encodes a polyubiquitin and the pSEN4 clone encodes a peptide related to endoxyloglucan transferase. This result is consistent with the expected roles of senescence-induced genes during leaf senescence.

Amino Acid Sequence↗

PubMed2000

Replicative senescence and oxidant-induced premature senescence. Beyond the control of cell cycle checkpoints.

Normal human diploid fibroblasts (HDFs) undergo replicative senescence inevitably in tissue culture after a certain number of cell divisions. A number of molecular changes observed in replicative senescent cells occur in somatic cells during the process of aging. Genetic studies on replicative senescence indicate the control of tumor suppression mechanisms. Despite the significance of replicative senescence in aging and cancer, little is known about the central cause of the complex changes observed in replicative senescent cells. The interest in the phenomenon has intensified in recent years, since damaging agents, certain oncogenes and tumor suppressor genes have been found to induce features of senescence in early passage young HDFs or in immortalized tumor cells. The reported features of senescence are summarized here in order to clarify the concept of replicative senescence or premature senescence. The experimental results of extending the replicative life span by reducing ambient oxygen tension or by N-tert-butyl-alpha-phenylnitrone (PBN) argue a role of oxidative damage in replicative senescence. By inducing premature senescence with a pulse treatment of H2O2, we can study the role of the cell cycle checkpoint proteins p53, p21, p16 and Rb in gaining each feature of senescence. Although p53 and Rb control G1 arrest and Rb appears to control cell enlargement, activation of the senescent associate beta-galactosidase, loss of cell replication and multiple molecular changes observed in premature senescent or replicative senescent cells are likely controlled by mechanisms beyond the cell cycle checkpoints.

Animals↗

PubMed2024

IGFBP7 is a key component of the senescence-associated secretory phenotype (SASP) that induces senescence in healthy cells by modulating the insulin, IGF, and activin A pathways.

Senescent cells exert their effects through the release of various factors, collectively referred to as the senescence-associated secretory phenotype (SASP). The SASP can induce senescence in healthy cells (secondary senescence), modulate immune system function, reshape the extracellular matrix, and facilitate cancer progression.Among SASP components, certain factors act as key regulators in the induction of secondary senescence. In this study, we evaluated the role of IGFBP7, a crucial SASP component. Our results demonstrated that ROS-prostaglandin signaling is involved in the release of IGFBP7. Furthermore, neutralizing antibodies targeting IGFBP7 attenuated the SASP's pro-senescence activity. Cells incubated with IGFBP7 also entered a state of senescence.The senescence induced by IGFBP7 appears to be mediated through three primary pathways. First, IGFBP7 can bind to insulin, thereby inhibiting its anti-senescence and pro-growth effects. In addition to this inhibitory effect on the insulin pathway, IGFBP7 may enhance IGFII pro-senescence signaling by promoting its interaction with IGF2R while blocking IGF1R. These activities are dependent on ERK and AKT signaling pathways. Finally, IGFBP7 and Activin A, both of which can induce cellular senescence, appear to regulate and inhibit each other, suggesting a compensatory mechanism to prevent excessive senescence. Notably, our preliminary data indicate that IGFBP7, in addition to blocking Activin A, may interact with its receptors and induce senescence via SMAD pathways.Our findings highlight that IGFBP7, along with other members of the IGFBP family, plays a pivotal role in senescence-related signaling pathways. Therefore, IGFBP7 may serve as a potential target for anti-aging strategies aimed at reducing the burden of senescence on tissues and organs.

Insulin-Like Growth Factor Binding Proteins↗

PubMed2006

Effect of sugar-induced senescence on gene expression and implications for the regulation of senescence in Arabidopsis.

There has been some debate whether leaf senescence is induced by sugar starvation or by sugar accumulation. External supply of sugars has been shown to induce symptoms of senescence such as leaf yellowing. However, it was so far not clear if sugars have a signalling function during developmental senescence. Glucose and fructose accumulate strongly during senescence in Arabidopsis thaliana (L.) Heynh. leaves. Using Affymetrix GeneChip analysis we determined the effect of sugar-induced senescence on gene expression. Growth on glucose in combination with low nitrogen supply induced leaf yellowing and changes in gene expression that are characteristic of developmental senescence. Most importantly, the senescence-specific gene SAG12, which was previously thought to be sugar-repressible, was induced over 900-fold by glucose. Induction of SAG12, which is expressed during late senescence, demonstrates that processes characteristic for late stages are sugar-inducible. Two MYB transcription factor genes, PAP1 and PAP2, were identified as senescence-associated genes that are induced by glucose. Moreover, growth on glucose induced genes for nitrogen remobilisation that are typically enhanced during developmental senescence, including the glutamine synthetase gene GLN1;4 and the nitrate transporter gene AtNRT2.5. In contrast to wild-type plants, the hexokinase-1 mutant gin2-1 did not accumulate hexoses and senescence was delayed. Induction of senescence by externally supplied glucose was partially abolished in gin2-1, indicating that delayed senescence was a consequence of decreased sugar sensitivity. Taken together, our results show that Arabidopsis leaf senescence is induced rather than repressed by sugars.

Anion Transport Proteins↗

PubMed2004

Leaf senescence is delayed in maize expressing the Agrobacterium IPT gene under the control of a novel maize senescence-enhanced promoter.

We have genetically modified maize plants to delay leaf senescence. A senescence-enhanced promoter from maize (P(SEE1)) was used to drive expression of the Agrobacterium cytokinin biosynthesis gene IPT in senescing leaf tissue. Three maize lines expressing IPT from P(SEE1), Sg1, Sg2 and Sg3, were analysed in detail, representing mild, intermediate and extreme expression, respectively, of the delayed-senescence phenotype. Backcross populations segregating for the presence or absence of the P(SEE1Xba)IPTNOS transgene also simultaneously segregated for the senescence phenotype. At the time of ear leaf emergence, individuals of lines Sg1 and Sg2 segregating for the presence of the transgene carried about three fewer senescing leaves than control (transgene-minus) segregants, and IPT transcript levels were higher in leaves at incipient senescence than in young leaves. Leaves of transgenic Sg3 plants were significantly greener than controls and progressed directly from fully green to bleached and dead without an intervening yellowing phase. IPT transcript abundance in this line was not related to the initiation of senescence. Extended greenness was accompanied by a delay in the loss of photosynthetic capacity with leaf age. The delayed-senescence trait was associated with relatively minor changes in morphology and development. The phenotype was particularly emphasized in plants grown in low soil nitrogen. The reduced ability of the extreme transgenic line Sg3 to recycle internal nitrogen from senescing lower leaves accounted for significant chlorosis in emerging younger leaves when plants were grown in low nutrient conditions. This study demonstrates that the agronomically important delayed-senescence ('stay-green') trait can be engineered into a monocot crop, and is the first example outside Arabidopsis of senescence modification using a homologous senescence-enhanced promoter.

Journal Article↗

PubMed2004

Senescent B lymphopoiesis is balanced in suppressive homeostasis: decrease in interleukin-7 and transforming growth factor-beta levels in stromal cells of senescence-accelerated mice.

The suppression of the B cell population during senescence has been considered to be due to the suppression of interleukin-7 (IL-7) production and responsiveness to IL-7; however, the upregulation of transforming growth factor-beta (TGF-beta) was found to contribute to B cell suppression. To investigate the mechanism of this suppression based on the interrelationship between IL-7 and TGF-beta during senescence, senescence-accelerated mice (SAMs), the mouse model of aging, were used in this study to elucidate the mechanisms of B lymphopoietic suppression during aging. Similar to regular senescent mice, SAMs showed a decrease in the number of IL-7-responding B cell progenitors (i.e., colony-forming unit pre-B [CFU-pre-B] cells in the femoral bone marrow [BM]). A co-culture system of B lymphocytes and stromal cells that the authors established showed a significantly lower number of CFU-pre-B cells harvested when BM cells were co-cultured with senescent stromal cells than when they were co-cultured with young stromal cells. Interestingly, cells harvested from a senescent stroma and those from the control culture without stromal cells were higher in number than those harvested from a young stroma, thereby implying that an altered senescent stromal cell is unable to maintain self-renewal of the stem cell compartment. Because TGF-beta is supposed to suppress the proliferative capacity of pro-B/pre-B cells, we added a neutralizing anti-TGF-beta antibody to the co-culture system with a pro-B/pre-B cell-rich population to determine whether such suppression may be rescued. However, unexpectedly, any rescue was not observed and the number of CFU-pre-B cells remained unchanged when BM cells were co-cultured with senescent stromal cells compared with the co-culture with young stromal cells, which essentially showed an increase in the number of CFU-pre-B cells (P < 0.001 in 5 microg/ml). Furthermore, TGF-beta protein level in the supernatant of cultured senescent stroma cells was evaluated by enzyme-linked immunoabsorbent assay, but surprisingly, it was found that TGF-beta concentration was significantly lower than that of cultured young stromal cells. Thus, TGF-beta activity was assumed to decline particularly in a senescent stroma, which means a distinct difference between the senescent suppression of B lymphopoiesis and secondary B lymphocytopenia. Concerning proliferative signaling, on the other hand, the level of IL-7 gene expression in cells from freshly isolated BM decreased significantly with age. Therefore, the acceleration of proliferative signaling and the deceleration of suppressive signaling may both be altered and weakened in a senescent stroma (i.e., homeosuppression).

Animals↗

PubMed2002

Stress-induced premature senescence or stress-induced senescence-like phenotype: one in vivo reality, two possible definitions?

No consensus exists so far on the definition of cellular senescence. The narrowest definition of senescence is irreversible growth arrest triggered by telomere shortening counting cell generations (definition 1). Other authors gave an enlarged functional definition encompassing any kind of irreversible arrest of proliferative cell types induced by damaging agents or cell cycle deregulations after overexpression of proto-oncogenes (definition 2). As stress increases, the proportion of cells in "stress-induced premature senescence-like phenotype" according to definition 1 or "stress-induced premature senescence," according to definition 2, should increase when a culture reaches growth arrest, and the proportion of cells that reached telomere-dependent replicative senescence due to the end-replication problem should decrease. Stress-induced premature senescence-like phenotype and telomere-dependent replicatively senescent cells share basic similarities such as irreversible growth arrest and resistance to apoptosis, which may appear through different pathways. Irreversible growth arrest after exposure to oxidative stress and generation of DNA damage could be as efficient in avoiding immortalisation as "telomere-dependent" replicative senescence. Probabilities are higher that the senescent cells (according to definition 2) appearing in vivo are in stress-induced premature senescence rather than in telomere-dependent replicative senescence. Examples are given suggesting these cells affect in vivo tissue (patho)physiology and aging.

Aging↗

PubMed1997

Isolation of cDNA clones for genes showing enhanced expression in barley leaves during dark-induced senescence as well as during senescence under field conditions.

Senescence of barley (Hordeum vulgare L. cv. Carina) primary foliage leaves was induced by transfer of the plants into darkness for 2 d. Under these conditions senescence was characterized by a light-reversible decline in the efficiency of photosystem II, and in chlorophyll and protein contents. To isolate senescence-associated genes a differential display of cDNA fragments amplified from reversely transcribed RNA was employed. By this method, gene expression in leaves of control plants collected at the onset of the dark period was compared with gene expression in senescing leaves collected at the end of the extended dark period. The expression of the genes represented by various differentially displayed cDNA fragments was examined by Northern blot hybridizations with RNA derived from primary foliage leaves before and after induction of senescence by darkness. In order to test whether these genes with enhanced expression during dark-induced senescence also show enhanced expression during natural senescence, Northern blot hybridizations were carried out with RNA samples prepared from flag leaves of barley plants during maturation and senescence under field conditions. Five of the cDNA fragments representing transcripts associated with dark-induced senescence, as well as with natural senescence, were selected as probes for screening a cDNA library from senescent flag leaves. With one probe a larger cDNA including a complete open reading frame with homology to the sequence of a known proteinase inhibitor was found. Another cDNA isolated by this means showed high sequence similarity with a gene coding for a 4-hydroxyphenylpyruvate dioxygenase. The other three larger cDNA clones isolated by this procedure so far do not show significant homologies with known sequences.

4-Hydroxyphenylpyruvate Dioxygenase↗

PubMed2005

Endogenous hormones and expression of senescence-related genes in different senescent types of maize.

Levels of cytokinins and abscisic acid (ABA) and the expression of senescence-related genes were investigated in two maize (Zea mays L.) cultivars of different senescence type, cv. P3845 (stay-green) and cv. Hokkou 55 (earlier senescent), in a field study. The delay in leaf senescence in P3845 was correlated with increased levels of chlorophyll and nitrogen and a higher photon-saturated photosynthetic rate (P(sat)). Compared with the earlier senescent Hokkou 55, P3845 showed enhanced contents of cytokinins (trans-zeatin riboside, t-ZR; dihydrozeatin riboside, DHZR; isopentenyladenosine, iPA) and reduced levels of ABA in its leaves. In roots, P3845 had increased levels of t-ZR, DHZR, and ABA, but decreased concentrations of iPA. It was concluded that a higher rate of cytokinin transport from roots to leaves contributes to the delay of senescence in P3845. By contrast, the translocation of ABA from roots to shoots may be blocked in the stay-green cultivar, which also results in retarded leaf senescence. P3845 ear leaves contained more malondialdehyde (MDA) and higher catalase (CAT) and superoxide dismutase (SOD) activities than Hokkou 55. Since the accumulation of the mRNAs for Rubisco small subunit (rbcS), phosphoenolpyruvate carboxylase (PEPC), and SOD peaked after Chl content and P(sat) had reached their maxima, it is speculated that when leaf senescence is initiated, Chl contents decrease first, followed by the degradation of the photosynthetic apparatus and of photosynthesis-related enzymes. See1 and See2 encode senescence-related cysteine proteases; their mRNAs were most abundant in yellowing leaves, suggesting that these proteins are involved in the process of senescence rather than its initiation. mRNAs of both genes were more abundant in Hokkou 55 than in P3845, which suggests a regulation of leaf senescence at the transcriptional level.

Abscisic Acid↗

PubMed1999

Leaf senescence is delayed in tobacco plants expressing the maize homeobox gene knotted1 under the control of a senescence-activated promoter.

Leaf senescence is an active process involving remobilization of nutrients from senescing leaves to other parts of the plant. Whereas senescence is accompanied by a decline in leaf cytokinin content, supplemental cytokinin delays senescence. Plants that overexpress isopentenyl transferase (ipt), a cytokinin-producing gene, or knotted1 (kn1), a homeobox gene, have many phenotypes in common. Many of these phenotypes are characteristic of altered cytokinin physiology. The effect of kn1 on leaf senescence was tested by driving its expression using the promoter of the senescence-associated gene SAG12. SAG:kn1 tobacco plants showed a marked delay in leaf senescence but otherwise developed normally. The delay in senescence was revealed by an increase in chlorophyll content in SAG:kn1 leaves relative to leaves of the control plants and by a decrease in the number of dead leaves. Senescence was also delayed in detached leaves of SAG:kn1 plants. Delayed senescence was accompanied by increased leaf cytokinin content in older leaves expressing kn1. These experiments extend the current understanding of kn1 function and suggest that in addition to mediating meristem maintenance, kn1 is capable of regulating the onset of senescence in leaves.

Aging↗

PubMed2003

Metabolic analysis of senescent human fibroblasts reveals a role for AMP in cellular senescence.

Cellular senescence is considered a major tumour-suppressor mechanism in mammals, and many oncogenic insults, such as the activation of the ras proto-oncogene, trigger initiation of the senescence programme. Although it was shown that activation of the senescence programme involves the up-regulation of cell-cycle regulators such as the inhibitors of cyclin-dependent kinases p16INK4A and p21CIP-1, the mechanisms underlying the senescence response remain to be resolved. In the case of stress-induced premature senescence, reactive oxygen species are considered important intermediates contributing to the phenotype. Moreover, distinct alterations of the cellular carbohydrate metabolism are known to contribute to oncogenic transformation, as is best documented for the phenomenon of aerobic glycolysis. These findings suggest that metabolic alterations are involved in tumourigenesis and tumour suppression; however, little is known about the metabolic pathways that contribute to these processes. Using the human fibroblast model of in vitro senescence, we analysed age-dependent changes in the cellular carbohydrate metabolism. Here we show that senescent fibroblasts enter into a metabolic imbalance, associated with a strong reduction in the levels of ribonucleotide triphosphates, including ATP, which are required for nucleotide biosynthesis and hence proliferation. ATP depletion in senescent fibroblasts is due to dysregulation of glycolytic enzymes, and finally leads to a drastic increase in cellular AMP, which is shown here to induce premature senescence. These results suggest that metabolic regulation plays an important role during cellular senescence and hence tumour suppression.

Adenosine Monophosphate↗

PubMed2001

Differential expression of thymosin beta-10 by early passage and senescent vascular endothelium is modulated by VPF/VEGF: evidence for senescent endothelial cells in vivo at sites of atherosclerosis.

VPF/VEGF acts selectively on the vascular endothelium to enhance permeability, induce cell migration and division, and delay replicative senescence. To understand the changes in gene expression during endothelial senescence, we investigated genes that were differentially expressed in early vs. late passage (senescent) human dermal endothelial cells (HDMEC) using cDNA array hybridization. Early passage HDMEC cultured with or without VPF/VEGF overexpressed 9 and underexpressed 6 genes in comparison with their senescent counterparts. Thymosin beta-10 expression was modulated by VPF/VEGF and was strikingly down-regulated in senescent EC. The beta-thymosins are actin G-sequestering peptides that regulate actin dynamics and are overexpressed in neoplastic transformation. We have also identified senescent EC in the human aorta at sites overlying atherosclerotic plaques. These EC expressed senescence-associated neutral beta-galactosidase and, in contrast to adventitial microvessel endothelium, exhibited weak staining for thymosin beta-10. ISH performed on human malignant tumors revealed strong thymosin beta-10 expression in tumor blood vessels. This is the first report that Tbeta-10 expression is significantly reduced in senescent EC, that VPF/VEGF modulates thymosin beta-10 expression, and that EC can become senescent in vivo. The reduced expression of thymosin beta-10 may contribute to the senescent phenotype by reducing EC plasticity and thus impairing their response to migratory stimuli.

Actins↗

PubMed2005

Expression of the Leo1-like domain of replicative senescence down-regulated Leo1-like (RDL) protein promotes senescence of 2BS fibroblasts.

Replicative senescence is thought to relate to aging in vivo and tumor suppression. In this report, we isolated a gene and designated it as RDL (replicative senescence down-regulated Leo1-like gene). RDL's expression decreased upon replicative senescence of human diploid 2BS fibroblasts. Overexpression of RDL slightly delayed 2BS fibroblast senescence, whereas suppression of RDL expression imposed no obvious effects on senescence. However, introduction of cDNA fragment encoding the Leo1-like domain of RDLp (Leo) alone shortened the replicative life span of 2BS fibroblasts and promoted several senescent features; the introduction of truncated RDL cDNA fragment resulting from deletion of Leo (RDL-Leo-) significantly prolonged 2BS life span and caused a noticeable delay of these senescent features. We demonstrated that introduction of Leo obviously increased the expression of p16INK4a, p21WAF1, and PTEN, whereas introduction of RDL-Leo- distinctly decreased p16INK4a expression. Taken together, our results suggest that the Leo1-like domain of RDLp is a senescence-associated domain that accelerates the senescence of 2BS fibroblasts and that there should be another counteractive domain in the remaining part of RDLp.

Blotting, Northern↗

PubMed1997

Senescence-related change in autologous mixed-lymphocyte reaction in senescence-accelerated mice.

Using the senescence-accelerated mouse (SAM) strains, we examined the senescence-related changes of autologous mixed-lymphocyte reaction (AMLR) as well as the phenotypic alteration of the T cell subsets. Splenic T cells from senescence-prone (SAM-P) and resistant (SAM-R) strains of mice were incubated with autologous non-T cells, and AMLR was measured on day 1-5. The kinetics of AMLR responses revealed a marked alteration in senescent SAM-P but not in non-senescent SAM-R mice, in which the peak response occurred at day 1, the response decreasing thereafter up to day 5. Similar senescence-related change was observed in aged (24-month-old) SAM-R and BALB/c mice. Furthermore, the T cells from the aged SAM-R mice cultured with non-senescent syngeneic non-T cells showed a very similar pattern to that cultured with autologous non-T cells. Flow cytometric analysis of T cell phenotype indicated that the percentage of CD4+ CD45RBhi T cells correlated with the peak AMLR responses in both SAM-P and SAM-R mice, and that the percentage of the T cell subset with extrathymic properties was significantly higher in SAM-P mice. These findings suggest that the alteration in kinetics of AMLR is related to senescence but not to the strain of mice, and may reflect a senescence-related dysfunction of the autoregulatory immune mechanisms of T cells.

Aging↗

PubMed2001

Senescence and cytoskeleton: overproduction of vimentin induces senescent-like morphology in human fibroblasts.

One characteristic feature of senescent fibroblasts is flat, enlarged, and heterogeneous cell shapes. The present study was aimed to understand the structural basis of the senescent cell morphology. SDS-gel electrophoresis as well as western blotting demonstrated that there occurred a prominent protein band about 57 kDa in the senescent cells as compared with normal young or immortalized cells growing rapidly, and the protein was identified with a cytoskeletal protein, vimentin. In fact, senescent fibroblasts contained approximately threefold more vimentin protein, and fourfold more vimentin mRNA than young embryonic fibroblasts. In the senescent cells, vimentin cytoskeleton occurred as densely bundled filaments in parallel with the long axis of cell bodies, whereas in young or actively growing cells it showed short and thin vimentin filaments or fur-like irregular networks. It was further demonstrated that senescent cell shapes could be induced when a vimentin expression construct was transfected in young fibroblasts. These results suggest that senescent fibroblasts overproduce vimentin protein, and the overproduced vimentin filaments bring about the senescent cell morphology.

Adult↗

PubMed2002

Identification of 30 protein species involved in replicative senescence and stress-induced premature senescence.

Exposure of human proliferative cells to subcytotoxic stress triggers stress-induced premature senescence (SIPS) which is characterized by many biomarkers of replicative senescence. Proteomic comparison of replicative senescence and stress-induced premature senescence indicates that, at the level of protein expression, stress-induced premature senescence and replicative senescence are different phenotypes sharing however similarities. In this study, we identified 30 proteins showing changes of expression level specific or common to replicative senescence and/or stress-induced premature senescence. These changes affect different cell functions, including energy metabolism, defense systems, maintenance of the redox potential, cell morphology and transduction pathways.

Base Sequence↗

PubMed2005

The identification of senescence-specific genes during the induction of senescence in prostate cancer cells.

Classic mechanisms of tumor response to chemotherapy include apoptosis and mitotic catastrophe. Recent studies have suggested that cellular senescence, a terminal proliferation arrest seen in vitro, may be invoked during the exposure of cancer cells to chemotherapeutic agents. To identify markers associated specifically with the cellular senescence phenotype, we utilized expression data from cDNA microarray experiments identifying transcripts whose expression levels increased as human prostate epithelial cells progressed to senescence. When screened against other growth-inhibitory conditions, including quiescence and apoptosis, many of these transcripts were also upregulated, indicating that similar pathways occur between apoptosis and senescence. A senescent-like phenotype was then induced in several prostate cancer cell lines using 5-aza-2'-deoxycytidine, doxorubicin, or Docetaxel. Treatment with these agents resulted in a significant increase in the induction of senescence-specific genes when compared to nonsenescent conditions. The performance of the panel was improved with fluorescence-activated cell sorting using PKH26 to isolate nonproliferating, viable, drug-treated populations, indicating that a heterogeneous response occurs with chemotherapy. We have defined an RNA-based gene panel that characterizes the senescent phenotype induced in cancer cells by drug treatment. These data also indicate that a panel of genes, rather than one marker, needs to be utilized to identify senescence.

Antineoplastic Agents↗

PubMed2005

Senescence-associated alterations of cytoskeleton: extraordinary production of vimentin that anchors cytoplasmic p53 in senescent human fibroblasts.

The cytoskeleton of senescent cells was systematically studied using senescent and young fibroblasts. In the cell senescence, skin fibroblasts extraordinarily produced vimentin in contrast to actin and tubulin, which were down-regulated. Among the focal adhesion proteins, paxillin and c-Src decreased also. Senescent cells developed a long and dense vimentin network, long and thin actin fibers, and numerous small focal contact sites, which contrasted with young cells with short and thick actin stress fibers and prominently large focal adhesions. Noticeably, senescent fibroblasts markedly produced p53 molecules and anchored them to vimentin-cytoskeleton in the cytoplasm. The vimentin-anchored p53 was detected with antibody PAb240 that specifically recognizes a conformation variant of p53. A GFP-tagged wild type p53 cDNA was expressed by transfection and shown also to be retained in the cytoplasm in senescent cells, suggesting that p53 is structurally modified to be recognized by PAb240 and anchored to vimentin filaments. We discuss the correlation of the marked alteration of cytoskeleton and senescent cells' diminished proliferation and migration, as well as the significance of cytoskeletal anchorage of tumor suppressor p53.

Actins↗