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)

We studied mechanisms by which senescent cells acquire resistance to UV-induced cellular insults. Human primary foreskin fibroblast culture was used since it undergoes cellular senescence in vitro after a limited number of passages. Senescence was induced by a brief treatment of the early passage cells with 100 microM of H2O2 for 1 h, and subsequent culture for 3 weeks. Hydrogen peroxide-treated cells showed an enhancement of senescence-associated beta-galactosidase activity. In the senescent cells, DNA fragmentation in response to UV-irradiation was found to decrease significantly compared with that in the young cells. The SAPK/JNK activation by UV irradiation was reduced in both non-treated senescent cells and the hydrogen peroxide-induced senescent cells, suggesting that a reduced DNA fragmentation by UV-irradiation in the senescent cells is closely related to the decreased SAPK/JNK activity. Since a cell cycle inhibitor, p21Waf1, has been implicated in protecting cells against apoptotic cell death, we determined p21Waf1 to assess whether its elevation has any impact on the reduction of UV-induced activation of SAPK/JNK in the senescent cells. The expression of p21Waf1 increased in both the nontreated and the hydrogen peroxide-treated senescent cells. Our study also revealed that the blockage of SAPK/JNK activation in the senescent cells was closely related to the increased level of p21Waf1. Our observation might provide clues about molecular mechanism of resistance to DNA fragmentation and the consequent cell death by UV-irradiation.
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PMID:Reduction of UV-induced cell death in the human senescent fibroblasts. 1098 39

Apoptosis Signal-regulating Kinase 1 (ASK1) is known to either induce apoptosis or differentiation in various cell lines of neuronal origin. We analyzed the effect of the constitutively active mutant of ASK1 (ASK1-Delta N) in an adenoviral vector in four neuroblastoma cell lines, two murine, C1300 and NXS2, and two human, SH-SY5Y and IMR-32. Already after 24 h upon infection, C1300 and SH-SY5Y cells arrested in growth when judged by [(3)H]thymidine incorporation, and the majority of the cells demonstrated apoptotic appearance, which was confirmed by DNA-laddering in gel electrophoresis. In contrast, NXS2 and IMR-32 cell lines remained unaffected. Immunoblotting revealed strongly phosphorylated p38 MAPK accompanied by weakly phosphorylated JNK in C1300 and SH-SY5Y, whereas none of these kinases were activated by adenoviruses expressing the kinase negative ASK1 mutant or beta-galactosidase. There was no expression of phosphorylated kinases in IMR-32 cells, but NXS2 showed a faint band of phosphorylated p38 MAPK. Addition of the p38 MAPK specific inhibitor, SB203580, protected C1300 and SH-SY5Y cells from apoptosis induced by ASK1-Delta N. The anti-neoplastic agent, paclitaxel, activates ASK1 and JNK, and promotes the in vitro assembly of stable microtubules. Addition of 10 nM paclitaxel sensitised the NXS2 cell line to ASK1-induced cell death. Our results indicate that ASK1 induces apoptosis in neuroblastoma cells mainly via the p38 MAPK pathway, and resistant neuroblastoma cells can be sensitised to ASK1 by paclitaxel.
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PMID:ASK1 resistant neuroblastoma is deficient in activation of p38 kinase. 1159 1

Protein kinase C (PKC) epsilon and PKCdelta translocation in neonatal rat ventricular myocytes (NRVMs) is accompanied by subsequent activation of the ERK, JNK, and p38(MAPK) cascades; however, it is not known if either or both novel PKCs are necessary for their downstream activation. Use of PKC inhibitors to answer this question is complicated by a lack of isoenzyme specificity, and the fact that many PKC inhibitors stimulate JNK and p38(MAPK) activity. Therefore, replication-defective adenoviruses (Advs) encoding constitutively active (ca) mutants of PKCepsilon and PKCdelta were used to test if either or both of these PKCs are sufficient to activate ERKs, JNKs, and/or p38(MAPK) in NRVMs. Adv-caPKCepsilon infection (1 to 25 multiplicities of viral infection (MOI); 4 to 48 hours) increased total PKCepsilon levels in a time- and dose-dependent manner, with maximal expression observed 8 hours after Adv infection. Adv-caPKCepsilon induced a time- and dose-dependent increase in phosphorylated p42 and p44 ERKs, as compared with a control Adv encoding beta-galactosidase (Adv-nebetagal). Maximal ERK phosphorylation occurred 8 hours after Adv infection. In contrast, JNK was only minimally activated, and p38(MAPK) was relatively unaffected. Adv-caPKCdelta infection (1 to 25 MOI, 4 to 48 hours) increased total PKCdelta levels in a similar fashion. Adv-caPKCdelta (5 MOI) induced a 29-fold increase in phosphorylated p54 JNK, and a 15-fold increase in phosphorylated p38(MAPK) 24 hours after Adv infection. In contrast, p42 and p44 ERK were only minimally activated. Whereas neither Adv induced NRVM hypertrophy, Adv-caPKCdelta, but not Adv-caPKCepsilon, induced NRVM apoptosis. We conclude that the novel PKCs differentially regulate MAPK cascades and apoptosis in an isoenzyme-specific and time-dependent manner.
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PMID:Differential activation of mitogen-activated protein kinase cascades and apoptosis by protein kinase C epsilon and delta in neonatal rat ventricular myocytes. 1170 8

Hydroxyurea is commonly used to treat hematologic disorders and some type of solid tumors, but the mechanism for its therapeutic effect is not clearly known. In this study, we examined the effect of hydroxyurea on rat hepatoma McA-RH7777 cells, specifically, on the role of mitogen-activated protein (MAP) kinase signal transduction pathways and p21(Waf1), p27(Kip1) and p53. Rat hepatoma McA-RH7777 cells treated with hydroxyurea for 7 days, caused the inhibition of cell growth in a dose-dependent manner. But, this growth inhibition was not caused by necrosis or apoptosis but instead was associated with cell senescence-like change as evidenced by senescence associated-beta-galactosidase staining, and cells arrest at G1 phase of cell cycle. Phosphorylation of MAP kinases, such as ERK, JNK, and p38, was found to be decreased after treatment of cells with hydroxyurea. But, the expression of p21(Waf1) was increased, while p27(Kip1) and p53 were not detected in hydroxyurea treated rat hepatoma cells. Hydroxyurea treatment induced G1 arrest and a senescence-like changes in rat hepatoma McA-RH7777 cells may be the likely results of signal disruption of MAP kinases (ERK, JNK, and p38 MAP kinase) and p21(Waf1) over-expression.
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PMID:Involvement of mitogen-activated protein kinases and p21Waf1 in hydroxyurea-induced G1 arrest and senescence of McA-RH7777 rat hepatoma cell line. 1555 22

We studied the role of JNK1,2 stress-kinases in the regulation of premature senescence program, stimulated by the inhibitor of histone deacetylase, sodium butyrate (NaB). It was found, that the transformants EIA + cHa-ras selected from embryonic mouse fibroblasts with knockout jnk1,2 stress-kinase genes did not block the cell cycle after sodium butyrate treatment. The data on the cell cycle distribution and cell growth curves showed that even long term (during five days) NaB influence did not suppress proliferation. We did not also reveal any cellular hypertrophy and increase in SA-beta-galactosidase activity after NaB treatment. The data presented suggest that JNK stress-kinases are involved in sodium butyrate-induced senescence in E1A + cHa-Ras mouse transformants, and they are indicative of that JNK1,2 have tumor suppressor properties.
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PMID:[Sodium butyrate do not induce the program of premature senescence in transformants with JNK1,2 knockout]. 1914 Mar 43

Low or high doses of doxorubicin induce either senescence or apoptosis, respectively, in cardiomyocytes. The mechanism by which different doses of doxorubicin may induce different stress-response cellular programs is not well understood. A recent study showed that the level of telomere dysfunction may induce senescence or apoptosis. We investigated the pathways to both apoptosis and senescence in neonatal rat cardiomyocytes and in H9c2 cells exposed to a single pulsed incubation with low or high doses of doxorubicin. High-dose doxorubicin strongly reduces TRF2 expression while enhancing TRF1 expression, and it determines early apoptosis. Low-dose doxorubicin induces downregulation of both TRF2 and TRF1, and it also increases the senescence-associated-beta-galactosidase activity, downregulates the checkpoint kinase Chk2, induces chromosomal abnormalities, and alters the cell cycle. The involvement of TRF1 and TRF2 with apoptosis and senescence was assessed by short interfering RNA interference. The cells maintain telomere dysfunction and a senescent phenotype over time and undergo late death. The increase in the phase>4N and the presence of micronuclei and anaphase bridges indicate that cells die by mitotic catastrophe. p38 modulates TRF2 expression, whereas JNK and cytoplasmic p53 regulate TRF1. Pretreatment with specific inhibitors of MAPKs and p53 may either attenuate the damage induced by doxorubicin or shift the cellular response to stress from senescence to apoptosis. In conclusion, various doses of doxorubicin induce differential regulation of TRF1 and TRF2 through p53 and MAPK, which is responsible for inducing either early apoptosis or senescence and late death due to mitotic catastrophe.
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PMID:Doxorubicin induces senescence or apoptosis in rat neonatal cardiomyocytes by regulating the expression levels of the telomere binding factors 1 and 2. 1980 96

Radiotherapy is increasingly used in the treatment of joint diseases, but limited information is available on the effects of radiation on cartilage. Here, we characterize the molecular mechanisms leading to cellular senescence in irradiated primary cultured articular chondrocytes. Ionizing radiation (IR) causes activation of ERK, in turn generating intracellular reactive oxygen species (ROS) with induction of senescence-associated beta-galactosidase (SA-beta-gal) activity. ROS activate p38 kinase, which further promotes ROS generation, forming a positive feedback loop to sustain ROS-p38 kinase signaling. The ROS inhibitors, nordihydroguaiaretic acid and GSH, suppress phosphorylation of p38 and cell numbers positive for SA-beta-gal following irradiation. Moreover, inhibition of the ERK and p38 kinase pathways leads to blockage of IR-induced SA-beta-gal activity via reduction of ROS generation. Although JNK is activated by ROS, this pathway is not associated with cellular senescence of chondrocytes. Interestingly, IR triggers down-regulation of SIRT1 protein expression but not the transcript level, indicative of post-transcriptional cleavage of the protein. SIRT1 degradation is markedly blocked by SB203589 or MG132 after IR treatment, suggesting that cleavage occurs as a result of binding with p38 kinase, followed by processing via the 26 S proteasomal degradation pathway. Overexpression or activation of SIRT1 significantly reduces the IR-induced senescence phenotype, whereas inhibition of SIRT1 activity induces senescence. Based on these findings, we propose that IR induces cellular senescence of articular chondrocytes by negative post-translational regulation of SIRT1 via ROS-dependent p38 kinase activation.
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PMID:Ionizing radiation induces cellular senescence of articular chondrocytes via negative regulation of SIRT1 by p38 kinase. 1988 52

We studied the role of p38 kinase and JNK1,2 in the activation of the complex mTORC1 and the program of senescence induced by histone deacetylase inhibitor, sodium butyrate (NaBut), in mouse embryonic fibroblasts transformed by E1A+cHa-Ras oncogenes. It was found that transformants from knockouts for the genes p38, were able to implement the program of NaBut-induced senescence, according to the data of the cell cycle arrest, inhibition of proliferation, hypertrophic changes associated with the activation of mTORC1 and SA-beta-galactosidase activity. According to the behavior of these markers, cell knockouts for the genes jnk1,2 were unable to implement NaBut-induced senescence. Induction of senescence closely correlates with the activation of the complex mTORC1, as it was shown by inhibiting mTORC1 with rapamycin. We believe that JNK 1,2 kinases are required for mTORC1 activation and acquiring the markers of premature senescence, induced by NaBut in the E1A+cHa-Ras transformants.
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PMID:[Involvement of MAP-kinase cascades into the regulation of sodium butyrate induced premature cell senescence]. 2346 Oct 35

Recent studies have revealed that adiponectin can suppress cellular inflammatory signaling pathways. This study aimed to elucidate the effect of adiponectin on the unregulated production of hBD2 in UVB-induced premature senescent keratinocytes. We constructed an in vitro model of premature senescent keratinocytes through repeated exposure to low energy UVB. After repeated low energy UVB exposure, there was significant generation of reactive oxygen species (ROS) and induction of senescence-associated markers, including senescence associated beta-galactosidase activity and expression of p16INK4a and histone H2AX. In addition, the present clinical study showed higher expression of hBD2 in sun-exposed skin of elderly group, and the overexpression of hBD2 was observed by c-Fos activation in vitro. Adiponectin has the ability to scavenge ROS and consequently inhibit MAPKs and SA-markers in UVB-exposed keratinocytes. An inhibitor study demonstrated that adiponectin downregulated hBD2 mRNA expression through suppression of the AP-1 transcription factor components c-Fos via inactivation of p38 MAPK. Collectively, the dysregulated production of hBD2 by the induction of oxidative stress was attenuated by adiponectin through the suppression of p38 and JNK/SAPK MAPK signaling in UVB-mediated premature senescent inducible conditions. These results suggest the feasibility of adiponectin as an anti-photoaging and anti-inflammatory agent in the skin.
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PMID:Adiponectin Suppresses UVB-Induced Premature Senescence and hBD2 Overexpression in Human Keratinocytes. 2759 49