Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.23 (beta-galactosidase)
 14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of age-related proliferative disorders of the prostate gland is supported by transdifferentiation and cellular senescence processes in the stroma. Both processes are involved in remodeling of stromal tissue, as observed in benign prostatic hyperplasia (BPH), and in "reactive stroma" adjacent to prostate cancer (PCa). It has been assumed that TGF-beta1 plays a key role in the aging prostate by inducing premature senescence and favoring myofibroblast differentiation. Therefore, we evaluated the stromal cell phenotypes of human primary adult prostatic fibroblasts (n=3) and the molecular and cellular mechanisms of growth arrest after treatment with TGF-beta1 and of in vitro cellular senescence. Microarray analysis, quantitative PCR, immunofluorescence and western blot revealed that cellular senescence and transdifferentiation of fibroblasts have distinct underlying mechanisms, pathways and gene and protein expression profiles in human PrSCs. In clear contrast to senescent cells, TGF-beta1-treated cells morphologically transdifferentiated into myofibroblasts with dense cytoskeletal fibers and increased expression of smooth muscle cell alpha-actin, calponin and tenascin. TGF-beta1 induced neither expression of senescence-associated markers nor genes involved in terminal growth arrest, such as senescence-associated beta-galactosidase and cyclin-dependent kinase (cdk) inhibitors p16(Ink4A) and p21(Cip1) but increased p15(Ink4B) protein expression. Differentiation inhibitor (Id-1) protein level down-regulation was observed under both conditions. Genes specifically up-regulated by transdifferentiation but not by cellular senescence of PrSCs were metalloproteinase 1 tissue inhibitor (Timp1), transgelin (Tagln), gamma 2 actin (Actg2), plasminogen activator inhibitor 1 (Serpinel), insulin-like growth factor binding protein 3 (Igfbp3), parathyroid hormone-like hormone (Pthlp), Tgfb-1, four and a half LIM domains 2 (Fhl-2), hydrogen peroxide-inducible clone 5 (Hic5) and cartilage oligomeric matrix protein (Comp). Other genes, such as Cdc28 protein kinase 1 (Cks1b), v-myb myeloblastosis viral oncogene homolog (MybL2), pyruvate kinase, muscle 2 (Pkm2) and Forkhead box M1 (FoxM1), were down-regulated only upon TGF-beta1 treatment but not by cellular senescence. Pyruvate dehydrogenase kinase 3 (Pdk3) and connective tissue growth factor (Ctgf) were up-regulated and hyaluronan synthase 3 (Has3) down-regulated under both conditions. Moreover, GageC1, a prostate/testis-specific protein overexpressed in symptomatic BPH and PCa was induced in transdifferentiated stromal cells. Genes such as GageC1 could be promising targets for therapeutic inhibitors of stromal tissue remodeling and progression of BPH and PCa.
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PMID:Profiling molecular targets of TGF-beta1 in prostate fibroblast-to-myofibroblast transdifferentiation. 1561 Jul 63

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.
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PMID:Frequent cellular senescence in small bile ducts in primary biliary cirrhosis: a possible role in bile duct loss. 1568 90

Hematopoietic cells are often exposed to transient hypoxia as they develop and migrate between blood and tissues. We tested the hypothesis that hypoxia-then-reoxygenation represent a stress for hematopoietic progenitor cells. Here we report that reoxygenation-generated oxidative stress induced senescence, tested as staining for SA-beta-galactosidase (SA-beta-gal), of bone marrow progenitor cells. Reoxygenation induced significant DNA damage and inhibited colony formation in lineage-depleted bone marrow cells enriched for progenitor cells. These reoxygenated cells exhibited a prolonged G(0)/G(1) accumulation without significant apoptosis after 24 h of treatments. Reoxygenated bone marrow progenitor cells expressed SA-beta-gal and senescence-associated proteins p53 and p21(WAF1). Reoxygenated Fancc-/- progenitor cells, which underwent significant apoptosis and senescence, tested as staining for SA-beta-gal, also expressed p16(INK4A). Suppression of apoptosis by the pan-caspase inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone dramatically increased senescent Fancc-/- progenitor cells. Senescence induction, tested as staining for SA-beta-gal, in reoxygenated progenitor cells was closely correlated with extent of DNA damage and phosphorylation of ATM at Ser-1981 and p53 at Ser-15. Moreover, inhibition of ATM signaling reduced SA-beta-gal positivity but increased apoptosis of reoxygenated progenitor cells. Thus, these results suggest that the ATM/p53/p21 pathway influences cell fate decision between apoptosis and senescence in reoxygenated hematopoietic progenitor cells.
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PMID:The ATM/p53/p21 pathway influences cell fate decision between apoptosis and senescence in reoxygenated hematopoietic progenitor cells. 1575 76

Hematopoietic cells are often exposed to transient hypoxia and reoxygenation as they develop and migrate. Given that bone marrow (BM) failure occurred in patients with Fanconi anemia (FA), we reason that hypoxia-then-reoxygenation represents a physiologically relevant stress for FA hematopoietic progenitor/stem cells. Here we show that expansion of Fancc-/- BM cells enriched for progenitor and stem cells was significantly decreased after 2 continuous cycles of hyperoxic-hypoxic-hyperoxic treatments compared with wild-type (WT) BM cells. This inhibition was attributable to a marked decrease of lineage-depleted (Lin-) ScaI- c-kit+ cells and more primitive Lin- ScaI+ c-kit+ cells in Fancc-/- BM cells following reoxygenation. Evaluation of the cell-cycle profile of long-term BM culture (LTBMC) revealed that a vast majority (70.6%) of reoxygenated Fancc-/- LTBMC cells was residing in the G0 and G1 phases compared with 55.8% in WT LTBMC cells. Fancc-/- LTBMC cells stained intensely for SA-beta-galactosidase activity, a biomarker for senescence; this was associated with increased expression of senescence-associated proteins p53 and p21(WAF1/CIP1). Taken together, these results suggest that reoxygenation induces premature senescence in Fancc-/- BM hematopoietic cells by signaling through p53, up-regulating p21, and causing senescent cell-cycle arrest. Thus, reoxygenation-induced premature senescence may be a novel mechanism underlying hematopoietic cell depletion and BM failure in FA.
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PMID:Hypoxia-reoxygenation induces premature senescence in FA bone marrow hematopoietic cells. 1576 96

Mesenchymal stem cell (MSC) has drawn much attention in the aspect of tissue renewal and wound healing because of its multipotency. We initially observed that bone marrow-derived human MSCs (hMSCs) divided poorly and took flat and enlarged morphology after expanded in culture over a certain number of cell passage, which resembled characteristic features of senescent cells, well-studied in human diploid fibroblasts (HDFs). More interestingly, adipogenic differentiation potential of hMSCs sharply declined as they approached the end of their proliferative life span. In this study, altered hMSCs were verified to be senescent by their senescence-associated beta-galactosidase (SA-beta-gal) activity and the increased expression of cell cycle regulating proteins (p16(INK4a), p21(Waf1) and p53). Similar as in HDFs, basal phosphorylation level of ERK was also significantly increased in senescent hMSCs, implying altered signal paths commonly shared by the senescent cells. Insulin, a major component of adipogenesis inducing medium, did not phosphorylate ERK 1/2 more in senescent hMSCs after its addition whereas it did in young cells. In senescent hMSCs, we also found a significant increase of caveolin-1 expression, previously reported as a cause for the attenuated response to growth factors in senescent HDFs. When we overexpressed caveolin-1 in young hMSC, not only insulin signaling but also adipogenic differentiation was significantly suppressed with down-regulated PPARgamma2. These data indicate that loss of adipogenic differentiation potential in senescent hMSC is mediated by the over-expression of caveolin-1.
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PMID:Increased caveolin-1, a cause for the declined adipogenic potential of senescent human mesenchymal stem cells. 1581 24

H2O2 has been the most commonly used inducer for stress-induced premature senescence (SIPS), which shares features of replicative senescence. However, there is still uncertainty whether SIPS and replicative senescence differ or utilize different pathways. 'Young' human diploid fibroblasts (HDFs), treated with prolonged low doses of hydrogen peroxide, led to irreversible cellular senescence. Cells exhibited senescent-morphological features, irreversible G1 cell cycle arrest and irreversible senescence-associated beta-galactosidase positivity. The appearance of these cellular senescence markers was accompanied by significant increases of p21, gadd45 expression and p53 binding activity, as well as a significant decline in DNA repair capability and accelerated telomere shortening. Our results suggest that multiple pathways might be involved in oxidative SIPS, including genes related to DNA-damage-and-repair and telomere shortening, and that SIPS shares the same mechanisms with replicative senescence in vivo. Our findings indicate that several aging theories can be merged together by a common mechanism of oxidative damage, and that the level of oxidative DNA-damage-and-repair capacity may be exploited as reliable markers of cell senescence.
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PMID:Irreversible cellular senescence induced by prolonged exposure to H2O2 involves DNA-damage-and-repair genes and telomere shortening. 1583 73

In this work, we described the proliferation of human non-small-cell-lung-cancer (NSCLC) cells H1437 harboring p53 alleles (proline-267) can be inhibited by low-dosage topoisomerase II inhibitor etoposide (VP-16) in vitro and in vivo. The cytotoxicity was demonstrated by prolonged cell arrest at G2-M checkpoint exhibiting senescence-like phenotype followed by apoptotic cell death that appeared on the sixth day of VP-16 treatment. The experimental in vivo evidence of growth suppression was also demonstrated in xenograft tumors. The appearance of senescence-like state during extended G2-M phase arrest was indicated by slow proliferation and loss of growth sensitivity in culture accompanied with cellular morphological changes, time-dependent regulation of beta-galactosidase staining as well as distinct reduction of telomerase activity upon protracted VP-16 exposure. Further molecular determinants leading to G2-M cell arrest was also characterized by the concerted up-regulation of cyclin-dependent kinase inhibitors, p16(INK4a) and p21(Waf1/Cipi), beginning 2 days later following drug exposure at both translational and transcriptional levels, while human telomerase reverse transcriptase (hTERT) activities reduced progressively. The clinically important therapeutic agent VP-16-mediated prolonged cell arrest at G2-M phase prior to apoptotic death offered a different perspective in restraining human cancer cells at low drug dosage, thereby serving as an effective telomerase inhibitor as well as an apoptosis effector. The overall results demonstrated that apoptosis can be regulated differently in human NSCLC cells with disrupted p53. Further effort in elucidating G2-M arrest before leading to apoptosis promises to provide an alternative insight in reversing tumorigenic phenotype of human cancers.
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PMID:Etoposide (VP-16) elicits apoptosis following prolonged G2-M cell arrest in p53-mutated human non-small cell lung cancer cells. 1589 59

Pretreatment of HepG2 and H1299 cells with chloramphenicol rendered the cells resistant to mitomycin-induced apoptosis. Both mitomycin-induced caspase 3 activity and PARP activation were also inhibited. The mitochondrial DNA-encoded Cox I protein, but not nuclear-encoded proteins, was down-regulated in chloramphenicol-treated cells. Cellular levels of the p21(waf1/cip1) protein and p21(waf1/cip1) mRNA were increased through a p53-independent pathway, possibly because of the stabilization of p21(waf1/cip1) mRNA in chloramphenicol-treated cells. The p21(waf1/cip1) was redistributed from the perinuclear region to the cytoplasm and co-localized with mitochondrial marker protein. Several morphological changes and activation of the senescence-associated biomarker, SA beta-galactosidase, were observed in these cells. Both p21(waf1/cip1) antisense and small interfering RNA could restore apoptotic-associated caspase 3 activity, PARP activation, and sensitivity to mitomycin-induced apoptosis. Similar effects were seen with other antibiotics that inhibit mitochondrial translation, including minocycline, doxycycline, and clindamycin. These findings suggested that mitochondrial stress causes resistance to apoptosis through a p21-dependent pathway.
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PMID:Chloramphenicol-induced mitochondrial stress increases p21 expression and prevents cell apoptosis through a p21-dependent pathway. 1590 68

Reactive oxygen species (ROS) were generated in all oxygen-utilizing organisms. Peroxiredoxin II (Prx II) as one of antioxidant enzymes may play a protective role against the oxidative damage caused by ROS. In order to define the role of Prx II in organismal aging, we evaluated cellular senescence in Prx II(-/-) mouse embryonic fibroblast (MEF). As compared to wild type MEF, cellular senescence was accelerated in Prx II(-/-) MEF. Senescence-associated (SA)-beta-galactosidase (Gal)-positive cell formation was about 30% higher in Prx II(-/-) MEF. N-Acetyl-l-cysteine (NAC) treatment attenuated SA-beta-Gal-positive cell formation. Prx II(-/-) MEF exhibited the higher G2/M (41%) and lower S (1.6%) phase cells as compared to 24% and 7.3% [corrected] in wild type MEF, respectively. A high increase in the p16 and a slight increase in the p21 and p53 levels were detected in PrxII(-/-) MEF cells. The cellular senescence of Prx II(-/-) MEF was correlated with the organismal aging of Prx II(-/-) mouse skin. While extracellular signal-regulated kinase (ERK) and p38 activation was detected in Prx II(-/-) MEF, ERK and c-Jun N-terminal kinase (JNK) activation was detected in Prx II(-/-) skin. These results suggest that Prx II may function as an enzymatic antioxidant to prevent cellular senescence and skin aging.
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PMID:Inhibitory role of peroxiredoxin II (Prx II) on cellular senescence. 1610 12

This study investigated the anticancer activity and related mechanisms of neolignans, especially threo, erythro-manassantin A (compound 2), which are isolated from Saururus chinensis, in PC-3 cells. Compound 2 strongly inhibited the proliferation of PC-3 cells in a dose-dependent manner. Different cell morphologies were observed depending on the concentration of compound 2, which suggested different growth inhibitory mechanisms. DNA flow cytometry indicated that both low and high concentrations of compound 2 induced the arrest of PC-3 cells in G1 phase. Western blot analyses showed that hyperphosphorylated Rb and E2F-1 were decreased, whereas hypophosphorylated Rb was increased. The cells treated with compound 2 at 200 ng/ml showed shrinkage morphologically, and the staining of annexin V-FITC revealed apoptotic cell death of these cells. The induction of apoptosis was accompanied by the cleavage of caspase-3, -8, and -9, as well as the downregulation of the Bcl-2 and the upregulation of Bax. By contrast, at low compound 2 concentration (1 ng/ml), the cells arrested in G1 showed characteristic changes in morphology, such as an enlarged, flattened cell shape; the majority strongly expressed SA-beta-galactosidase activity. The number of cells undergoing apoptosis was negligible, and no poly(ADP-ribose) polymerase (PARP) cleavage was observed. The increase of p21 was noticed. However, it appeared to be transient rather than sustained. The protein p27 may be important for maintaining the senescence machinery induced by compound 2 because p27 expression was increased at low concentration compared with that at high concentration. In conclusion, compound 2 showed a significant growth inhibitory effect in PC-3 cells via two different mechanisms, i.e., apoptosis at high concentration and senescence at low concentration.
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PMID:Neolignans from Saururus chinensis inhibit PC-3 prostate cancer cell growth via apoptosis and senescence-like mechanisms. 1614 81


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