Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic stellate cells are the major source of the extracellular matrix that accumulates in fibrotic liver. During progressive liver fibrosis, hepatic stellate cells proliferate, but during resolution of fibrosis there is extensive stellate cell apoptosis that coincides with degradation of the liver scar. We have examined the possibility that the fate of stellate cells is influenced by the extracellular matrix through the intermediary of alpha(v)beta(3) integrin. alpha(v)beta(3) integrin was expressed by activated, myofibroblastic rat and human stellate cells in culture. Antagonism of this integrin using neutralizing antibodies, echistatin, or small inhibitory RNA to silence alpha(v) subunit expression inhibited stellate cell proliferation and their expression of proliferating cell nuclear antigen and activated forms of p44 and p42 MAPK. These alpha(v)beta(3) antagonists also increased apoptosis of cultured stellate cells, and this was associated with an increase in the BAX/BCL-2 protein ratio, induction of nuclear DNA fragmentation, and activation of intracellular caspase-3. Expression of tissue inhibitor of metalloproteinases-1 by activated stellate cells was reduced by the alpha(v)beta(3) antagonists, while matrix metalloproteinase-9 synthesis was enhanced. Stellate cells incubated with active recombinant matrix metalloproteinase-9 showed enhanced apoptosis, while cells treated with a synthetic inhibitor of this protease showed increased survival. Our studies suggest that alpha(v)beta(3) integrin regulates the fate of hepatic stellate cells. Degradation of alpha(v)beta(3) ligands surrounding activated stellate cells during resolution of liver fibrosis might decrease alpha(v)beta(3) integrin ligation, suppressing stellate cell proliferation and inducing a fibrolytic, matrix metalloproteinase-secreting phenotype that may prime stellate cells for apoptosis.
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PMID:Engagement of alphavbeta3 integrin regulates proliferation and apoptosis of hepatic stellate cells. 1504 41

Our aim was to study the anticancer effect of the novel immunomodulator FTY720 in vitro and in vivo by investigation of cell cycle entry, cell cycle regulation, cell survival and apoptosis pathways. Three hepatoma cell lines with different p53 statuses (HepG2, Huh-7 and Hep3B) and one non-tumorigenic immortalized liver cell line (MIHA) were used for an in vitro study. The in vivo effects of FTY720 were evaluated in a nude mouse tumor model. Cell cycle distribution and cell cycle regulator proteins p27(Kip1) and cyclin D1, together with the PI3-K/Akt pathway, mitogen-activated protein kinases and cleaved caspase-3 and caspase-9, were evaluated. FTY720 selectively induced cell apoptosis in hepatoma cell lines with overexpression of cleaved caspase-3 and caspase-9, but the same phenomena were not found in MIHA cells. FTY720 induced Akt dephosphorylation at Ser473 mediated by phosphoinositide 3-kinase (PI3-K) inhibition. Dephosphorylation led to down-regulation of p42/p44 and dephosphorylation of Forkhead transcription factor and GSK-3beta and, subsequently, up-regulation of p27(Kip1) and down-regulation of cyclin D1. In our in vivo model FTY720 induced apoptosis of tumor cells by down-regulation of the Akt pathway. FTY720 suppressed tumor growth without notable side-effects in normal liver. In conclusion, FTY720 is a novel anticancer agent that induces apoptosis of hepatoma cell lines both in vitro and in vivo through PI3-K-mediated Akt dephosphorylation in a p53-independent manner.
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PMID:FTY720 induces apoptosis of human hepatoma cell lines through PI3-K-mediated Akt dephosphorylation. 1529 71

A key feature in the molecular pathogenesis of liver fibrosis requires maintenance of the activated hepatic stellate cell (HSC) phenotype by both proliferation and inhibition of apoptosis. We provide evidence that leptin is a potent HSC mitogen and dramatically inhibits stellate cell apoptosis. Leptin proved to be as potent an HSC mitogen as platelet-derived growth factor (PDGF) as assessed by bromodeoxyuridine (BrdU) incorporation in isolated primary HSCs; data using fluorescent propidium iodide (PI) uptake revealed that leptin, like PDGF, increased HSC populations in the S- and G2/M-phases of the cell cycle. Leptin resulted in a robust increase in cyclin D1 expression. Using the chemical inhibitor of Janus kinase 2 (Jak2) activity, AG 490, and overexpression of the suppressor of cytokine signaling 3 (SOCS-3), we show that blockade of leptin receptor (Ob-Rb) phosphorylation blocks leptin-induced HSC proliferation. Leptin-associated phosphorylation of both extracellular regulated kinase (p44/p42, Erk) and Akt is also prohibited. Further, the PI-3 kinase inhibitor LY294002 and MAPK inhibitor PD98059 were found to significantly reduce leptin-induced HSC proliferation, thereby indicating that leptin induced HSC proliferation is Akt- and Erk-dependent. Akt was also protective against HSC apoptosis. Leptin abolished both cycloheximide-induced and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, demonstrated by reduced caspase-3 activity, HSC-TUNEL staining, and DNA fragmentation. We conclude that leptin acts as a direct hepatic stellate cell survival agonist. Importantly, we have demonstrated that leptin-induced HSC proliferation and survival by Ob-Rb phosphorylation are both Erk- and Akt-dependent.
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PMID:Leptin as a novel profibrogenic cytokine in hepatic stellate cells: mitogenesis and inhibition of apoptosis mediated by extracellular regulated kinase (Erk) and Akt phosphorylation. 1531 73

Mitogen-activated protein kinase (MAPK) cascades are membrane-to-nucleus signaling modules that recently have been implicated as mediators of cellular injury. In this study, we investigated the involvement of the MAP kinase p44/p42 (extracellular signal-regulated kinase [ERK1/2]) in traumatic brain injury (TBI) in rats. There was a strong increase in activated, phosphorylated ERK 1/2 (p-ERK 1/2) protein at 10 min up to 24 h after the injury. Expression of p-ERK occurred in cells identified as neurons, astrocytes, and microglia. Most of the cells expressing p-ERK were TUNEL positive at later time points. Treatment with the MEK inhibitor U0126 or the free radical scavenger S-PBN, both with neuroprotective properties in TBI, attenuated the early activation of ERK and resulted in less activation of caspase-3 and subsequent DNA fragmentation. Post-treatment with U0126 resulted in a significant decrease (-60%) in cortical cavity size and cortical atrophy at 2 weeks after trauma. Overall, the results suggest that ERK activation is initiated by increased oxygen radical activity and that overactivation of ERK sets off secondary cell death mechanisms in TBI. Clinical studies are warranted to evaluate the concept of MEK inhibition in head-injured patients.
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PMID:Oxygen free radical-dependent activation of extracellular signal-regulated kinase mediates apoptosis-like cell death after traumatic brain injury. 1545 87

Despite significant evidence of a role of hypoxia in cellular resistance to ionizing radiation-induced toxicity, the underlying molecular mechanisms remain unclear. This study focused on the influence of hypoxia on radiation-induced signals in TK6 human lymphoblastoid cells. Hypoxic (<10 ppm oxygen) and aerobic cells were exposed to equilethal doses of ionizing radiation, radiation dose ratio, 3:1 (hypoxia:air). Hypoxia alone or radiation treatment under aerobic or hypoxic conditions led to increased levels of phospho-p44/42 mitogen-activated protein kinase. Levels of phospho-p38 mitogen-activated protein kinase did not change as a result of either hypoxia or irradiation. Hypoxia alone had no effect on expression of phospho-stress-activated protein kinase (SAPK), wild-type p53, or cleaved caspase 3. Irradiation under aerobic conditions resulted in an increase in the phospho-SAPK signal, whereas hypoxia suppressed the irradiation-induced increase in the level of phospho-SAPK. Both hypoxic and aerobic cells showed increases in p53 levels in response to radiation. Hypoxia blocked radiation-induced cleavage of caspase 3 and poly-ADP-ribose polymerase. Irradiation of aerobic and hypoxic TK6 cells using 6 and 18 Gy, respectively, resulted in a similar and significant increase in fraction of apoptotic cells within 24 hours postirradiation. In contrast, basal levels of apoptosis were observed at 24 hours postirradiation in aerobic and hypoxic NH32 cells, a p53 null derivative of TK6 cells. These results suggest that radiation-induced apoptosis under hypoxia occurs independent of phospho-SAPK and caspase 3, and the p53 response is an obligatory apoptotic signal in TK6 cells.
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PMID:Effects of hypoxia on radiation-responsive stress-activated protein kinase, p53, and caspase 3 signals in TK6 human lymphoblastoid cells. 1569 2

BACKGROUND: Neutrophils represent the first line of defence against aggressions. The programmed death of neutrophils is delayed by pro-inflammatory stimuli to ensure a proper resolution of the inflammation in time and place. The pro-inflammatory stimuli include granulocyte-macrophage colony-stimulating factor (GM-CSF). Recently, we have demonstrated that although neutrophils have an identical spontaneous apoptosis in elderly subjects compared to that in young subjects, the GM-CSF-induced delayed apoptosis is markedly diminished. The present study investigates whether an alteration of the GM-CSF stimulation of MAPKs play a role in the diminished rescue from apoptosis of PMN of elderly subjects. METHODS: Neutrophils were separated from healthy young and elderly donors satisfying the SENIEUR protocol. Neutrophils were stimulated with GM-CSF and inhibitors of the MAPKinase pathway. Apoptosis commitment, phosphorylation of signaling molecules, caspase-3 activities as well as expression of pro- and anti-apoptotic molecules were performed in this study. Data were analyzed using Student's two-tailed t-test for independent means. Significance was set for p </= 0.05 unless stated otherwise. RESULTS: In this paper we present evidence that an alteration in the p42/p44 MAPK activation occurs in PMN of elderly subjects under GM-CSF stimulation and this plays a role in the decreased delay of apoptosis of PMN in elderly. We also show that p38 MAPK does not play a role in GM-CSF delayed apoptosis in PMN of any age-groups, while it participates to the spontaneous apoptosis. Our results also show that the alteration of the p42/p44 MAPK activation contributes to the inability of GM-CSF to decrease the caspase-3 activation in PMN of elderly subjects. Moreover, GM-CSF converts the pro-apoptotic phenotype to an anti-apoptotic phenotype by modulating the bcl-2 family members Bax and Bcl-xL in PMN of young subjects, while this does not occur in PMN of elderly. However, this modulation seems MAPK independent. CONCLUSION: Our results show that the alteration of p42/p44 MAPK activation contributes to the GM-CSF induced decreased PMN rescue from apoptosis in elderly subjects. The modulation of MAPK activation in PMN of elderly subjects might help to restore the functionality of PMN with aging.
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PMID:The role of the MAPK pathway alterations in GM-CSF modulated human neutrophil apoptosis with aging. 1574 27

We have shown previously that LPPs (lipid phosphate phosphatases) reduce the stimulation of the p42/p44 MAPK (p42/p44 mitogen-activated protein kinase) pathway by the GPCR (G-protein-coupled receptor) agonists S1P (sphingosine 1-phosphate) and LPA (lysophosphatidic acid) in serum-deprived HEK-293 cells [Alderton, Darroch, Sambi, McKie, Ahmed, N. J. Pyne and S. Pyne (2001) J. Biol. Chem. 276, 13452-13460]. In the present study, we now show that this can be blocked by pretreating HEK-293 cells with the caspase 3/7 inhibitor, Ac-DEVD-CHO [N-acetyl-Asp-Glu-Val-Asp-CHO (aldehyde)]. Therefore LPP2 and LPP3 appear to regulate the apoptotic status of serum-deprived HEK-293 cells. This was supported further by: (i) caspase 3/7-catalysed cleavage of PARP [poly(ADP-ribose) polymerase] was increased in serum-deprived LPP2-overexpressing compared with vector-transfected HEK-293 cells; and (ii) serum-deprived LPP2- and LPP3-overexpressing cells exhibited limited intranucleosomal DNA laddering, which was absent in vector-transfected cells. Moreover, LPP2 reduced basal intracellular phosphatidic acid levels, whereas LPP3 decreased intracellular S1P in serum-deprived HEK-293 cells. LPP2 and LPP3 are constitutively co-localized with SK1 (sphingosine kinase 1) in cytoplasmic vesicles in HEK-293 cells. Moreover, LPP2 but not LPP3 prevents SK1 from being recruited to a perinuclear compartment upon induction of PLD1 (phospholipase D1) in CHO (Chinese-hamster ovary) cells. Taken together, these data are consistent with an important role for LPP2 and LPP3 in regulating an intracellular pool of PA and S1P respectively, that may govern the apoptotic status of the cell upon serum deprivation.
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PMID:Regulation of cell survival by lipid phosphate phosphatases involves the modulation of intracellular phosphatidic acid and sphingosine 1-phosphate pools. 1596 Jun 10

Although epidemiological studies indicate an association between elevations in fecal bile acids and the development of colorectal cancer, the cellular mechanism for the proliferative actions of bile acids is not clear. Studies from other laboratories indicate a paradoxical pro-apoptotic action of bile acids on cell culture lines. Our previous studies indicate that cholinergic agonist-induced proliferation of colon cancer cells that express M3 muscarinic receptors (M3R) is mediated by transactivation of the epidermal growth factor receptor (EGFR) and that bile acids stimulate proliferation of colon cancer cells that express M3R. In the present study, we investigated the effects of bile acids on cell signaling and proliferation of a human colon cancer cell line (H508 cells) that abundantly expresses M3R and EGFR. Treatment with taurine and glycine conjugates of lithocholic and deoxycholic acids stimulated reversible activation of the p44/42 MAP kinase signaling cascade and proliferation of H508 cells. Bile acids did not stimulate proliferation of SNU-C4 colon cancer cells that express EGFR but not muscarinic receptors. Atropine, a muscarinic receptor inverse agonist, blocked bile acid-induced H508 cell proliferation. At concentrations that stimulate cell proliferation, conjugated bile acids did not activate caspase-3, a key mediator of apoptosis. Conjugated bile acids stimulated phosphorylation of EGFR Tyr992, thereby implicating EGFR transactivation in the cellular mechanism underlying their proliferative actions. This was confirmed by observing that inhibitors of EGFR activation and antibodies to the ligand-binding domain of EGFR blocked both the signaling and proliferative actions of bile acids. Collectively, these results suggest that in this colon cancer cell line, bile acid-induced colon cancer cell proliferation is M3R-dependent and is mediated by transactivation of EGFR.
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PMID:Bile acid-induced proliferation of a human colon cancer cell line is mediated by transactivation of epidermal growth factor receptors. 1613 3

Tumor necrosis factor alpha (TNFalpha) can trigger both cell survival and apoptosis. In the present study, from the flow cytometry results, we found that the prolonged-treatment of TNFalpha until 24 h, resulted apoptosis in AM-1 cells (ameloblastoma cell line). These results were confirmed by DAPI staining, which showed nuclear fragmentation feature of AM-1 cells under treatment of TNFalpha. Our further investigation using specific caspase inhibitors showed that caspase-3 played a crucial role in mediating TNFalpha-induced apoptosis in AM-1 cells. In addition, significant elevation of TNFalpha potential in inducing apoptosis was seen by applying LY294002, phosphatidylinositol-3-OH kinase (PI3K) inhibitor, or U0126, mitogen-activated extracellular-regulated kinase (MEK1/2) inhibitor, prior to the treatment of TNFalpha in AM-1 cells. These results suggested that TNFalpha induced both cell survival and apoptosis pathways in ameloblastoma and potential of TNFalpha in inducing apoptosis can be improved by inhibiting TNFalpha-induced Akt and p44/42 mitogen-activated protein kinase (MAPK) cell survival pathways.
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PMID:Inhibition of Akt and MAPK pathways elevated potential of TNFalpha in inducing apoptosis in ameloblastoma. 1614 May 62

Cepharanthine (CEP), a biscoclaurine alkaloid, has been reported to induce cell death, however, the molecular mechanism of this phenomenon remains unclear. We herein report that CEP induced apoptosis in HuH-7 cells through nuclear fragmentation, DNA ladder formation, cytochrome c release, caspase-3 activation and poly-(ADP-ribose)-polymerase cleavage. CEP triggered the generation of reactive oxygen intermediates, the activation of mitogen activated protein kinase (MAPK) p38, JNK1/2 and p44/42, and the downregulation of protein kinase B/Akt. Antioxidants and SP600125, an inhibitor of JNK1/2, but not inhibitors of p38 MAPK and MEK1/2, significantly prevented cell death, thus implying that reactive oxygen species and JNK1/2 play crucial roles in the CEP-induced apoptosis of HuH-7 cells.
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PMID:Cepharanthine triggers apoptosis in a human hepatocellular carcinoma cell line (HuH-7) through the activation of JNK1/2 and the downregulation of Akt. 1641 24


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