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)

The activity of tumor necrosis factor (TNF), a proinflammatory cytokine, is regulated by a number of other cytokines, including interleukin (IL)-4. How IL-4 regulates various activities of TNF is not fully understood. In the present report, we investigated the effect of IL-4 on the cell surface TNF receptors in human histiocytic lymphoma U-937 cells. Pretreatment of cells with IL-4 down-regulated TNF receptors in a dose- and time-dependent manner; an almost 90% decrease occurred with 10 ng/ml IL-4 treatment for 24 h. Scatchard analysis revealed that the decrease was due to receptor number and not affinity. IL-13, which shares a common receptor subunit and various biological activities with IL-4, had no effect on TNF receptors. IL-4's effect on TNF receptors was not cell type-specific, since decreases also occurred on various epithelial and T cells. Both the p60 and p80 forms of the TNF receptor were down-regulated to the same extent. Western blot showed that IL-4 induced shedding of the TNF receptors. The decrease of TNF receptors by IL-4 was accompanied by down-regulation of TNF-induced activities, including cytotoxicity, caspase-3 activation, NF-kappaB and AP-1 activation, and c-Jun N-terminal kinase induction. Wortmannin reversed the IL-4-induced TNF receptor down-regulation and all other measured cellular responses, indicating a critical role of phosphatidylinositol 3-kinase. Rapamycin also blocked the effect of IL-4-induced regulation, thus suggesting the role of p70 S6 kinase. Overall, our results suggest that TNF receptor down-regulation by IL-4 plays a critical role in the antagonistic effects of IL-4 on TNF-induced cellular responses and that this mechanism differs from that of IL-13.
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PMID:Interleukin-4 down-regulates both forms of tumor necrosis factor receptor and receptor-mediated apoptosis, NF-kappaB, AP-1, and c-Jun N-terminal kinase. Comparison with interleukin-13. 983 7

Treatment of cells with DNA-damaging agents, such as etoposide, can cause growth arrest or apoptosis. Treatment of Swiss 3T3 or RAT-1 cells with etoposide led to the dephosphorylation of both p70 S6 kinase and eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1), resulting in decreased p70 S6 kinase activity and an increase in 4E-BP1 binding to eIF4E. These effects were not prevented by the general caspase inhibitor, Z-VAD.FMK. These findings indicate caspase-independent inhibition of signalling pathways that involve the mammalian target of rapamycin (mTOR). Similar effects were observed in response to two other DNA-damaging agents, cisplatin and mitomycin-C. These events preceded apoptosis, which was assessed by caspase-3 activity assays and FACS analysis. This shows that inhibition of mTOR signalling is not a consequence of apoptosis, although it may play a role in the events that precede cell death. 4E-BP1 was cleaved during apoptosis yielding a fragment that retained the ability to bind eIF4E. Cleavage of 4E-BP1 was inhibited by treatment of the cells with Z-VAD.FMK, indicating it is caspase-dependent. Insulin elicited full activation of p70 S6 kinase and phosphorylation of 4E-PB1 in etoposide-treated cells prior to the onset of apoptosis, but not during cell death. This suggests that mTOR signalling becomes irreversibly inhibited only after entry into apoptosis. Oncogene (2000).
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PMID:DNA-damaging agents cause inactivation of translational regulators linked to mTOR signalling. 1087 54

Treatment of Swiss 3T3 cells with staurosporine resulted in dephosphorylation of two proteins which play key roles in regulating mRNA translation. This occurred before the execution of apoptosis, assessed by caspase-3 activity. These translation regulators are p70 S6 kinase, which phosphorylates ribosomal protein S6, and eukaryotic initiation factor (eIF) 4E binding protein 1 (4E-BP1), which both lie downstream of the mammalian target of rapamycin (mTOR). This resulted in decreased p70 S6 kinase activity, dephosphorylation of ribosomal protein S6, increased binding of 4E-BP1 to eIF4E and a concomitant decrease in eIF4F complexes. Our data show that staurosporine impairs mTOR signalling in vivo but that this not due to direct inhibition of mTOR or to inhibition of protein kinase C. It is becoming clear that agents which cause apoptosis inactivate mTOR signalling as a common early response prior to the execution of apoptosis, i.e., before caspase activation.
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PMID:Staurosporine inhibits phosphorylation of translational regulators linked to mTOR. 1152 37

1. Previous studies have shown that the histamine H(1) receptor activates p42/p44 mitogen-activated protein kinases (MAPK) in DDT(1)MF-2 smooth muscle cells via a phosphatidylinositol 3-kinase (PI-3K)-dependent pathway. In this study the effect of histamine H(1) receptor stimulation on protein kinase B (PKB) and p70 S6 kinase, both of which are downstream targets of PI-3K, has been investigated. Increases in PKB and p70 S6 kinase activation were monitored by Western blotting using phospho-specific PKB (Ser(473)) and p70 S6 kinase (Thr(421)/Ser(424)) antibodies. 2. Histamine stimulated time and concentration-dependent increases in the phosphorylation of PKB and p70 S6 kinase in DDT(1)MF-2 cells. Both responses were completely inhibited by the histamine H(1) receptor antagonist mepyramine and following pre-treatment with pertussis toxin, to block G(i)/G(o) protein dependent pathways. 3. The PI-3K inhibitors wortmannin (IC(50) 5.9+/-0.5 nM) and LY 294002 (IC(50) 6.9+/-0.8 microM) attenuated the increase in PKB phosphorylation induced by histamine (100 microM) in a concentration-dependent manner. 4. Histamine-induced increases in p70 S6 kinase phosphorylation were partially sensitive to rapamycin (20 nM; 68% inhibition) but completely blocked by wortmannin (100 nM), LY 294002 (30 microM) and the MAPK kinase inhibitor PD 98059 (50 microM). 5. In summary, these data demonstrate that the histamine H(1) receptor stimulates PKB and p70 S6 kinase phosphorylation in DDT(1)MF-2 smooth muscle cells. However, functional studies revealed that histamine does not stimulate DDT(1)MF-2 cell proliferation or attenuate staurosporine-induced caspase-3 activity. The challenge for future research will be to link the stimulation of these kinase pathways with the physiological and pathophysiological roles of the histamine H(1) receptor.
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PMID:Stimulation of protein kinase B and p70 S6 kinase by the histamine H1 receptor in DDT1MF-2 smooth muscle cells. 1195

The aim of this study was to clarify the mechanism(s) of an inhibitory effect of cerivastatin on cultured rat vascular smooth muscle cell (VSMC) growth. After being starved, cultured VSMCs were stimulated by 5% fetal bovine serum with either various concentrations of cerivastatin or 10-4 M of mevalonate. Cerivastatin dose-dependently decreased the values of [3H]-thymidine incorporation and cell numbers and the level of phosphorylated extracellular signal-regulated protein kinase 1/2. It also suppressed the level of proliferative cell nuclear antigen in a dose-dependent manner. These reductions were abolished by the addition of mevalonate. Similarly, the level of phosphorylated p38 was also decreased by cerivastatin. In contrast, cerivastatin dose-dependently activated the phosphorylation of both c-jun NH2-terminal protein kinase and activating transcription factor-2, and these activations were abolished by the addition of mevalonate. The levels of phosphorylated Akt and p70 S6 kinase as well as those of Bcl-2 were dose-dependently reduced by cerivastatin, and these reductions were abolished by the addition of mevalonate. Cerivastatin could dose-dependently elevate the levels of CPP32/caspase-3 activity and cytoplasmic histone-associated DNA fragments in VSMCs without causing cytotoxicity. These results indicate that cerivastatin suppresses cell survival and activates the apoptotic cellular signaling in VSMCs, suggesting that it could be effective for preventing the progression of restenosis after angioplasty.
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PMID:Mechanisms of inhibitory effects of cerivastatin on rat vascular smooth muscle cell growth. 1213 57

Thyroid-stimulating hormone (TSH) action in adipose tissue remains largely unknown. Our previous work indicates that human preadipocytes express functional TSH receptor (TSHR) protein, demonstrated by TSH activation of p70 S6 kinase (p70 S6K). We have now studied murine 3T3-L1 preadipocytes to further characterize TSH signaling and cellular action. Western blot analysis of 3T3-L1 preadipocyte lysate revealed the 100-kDa mature processed form of TSHR. TSH activated p70 S6K and protein kinase B (PKB/Akt), as measured by immunoblot analysis. Preincubation with wortmannin or LY-294002 completely blocked TSH activation of p70 S6K and PKB/Akt, implicating phosphoinositide 3-kinase (PI3K) in their regulation. TSH increased phosphotyrosine protein(s) in the 125-kDa region and augmented the associated PI3K activity fourfold. TSH had no effect on cAMP levels in 3T3-L1 preadipocytes, suggesting that adenylyl cyclase is not involved in TSH activation of the PI3K-PKB/Akt-p70 S6K pathway. 3T3-L1 preadipocyte cell death was reduced by 29-76% in serum-deprived (6 h) preadipocytes treated with 1-20 microM TSH. In the presence of 20 microM TSH, an 88% reduction in terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL)-positive cells was observed in serum-starved (3 h) 3T3-L1 preadipocytes as well as a 93% reduction in the level of cleaved activated caspase 3. In summary, TSH acts as a survival factor in 3T3-L1 preadipocytes. TSH does not stimulate cAMP accumulation in these cells but instead activates a PI3K-PKB/Akt-p70 S6K pathway.
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PMID:TSH signaling and cell survival in 3T3-L1 preadipocytes. 1222 69

Acute vascular or humoral rejection, a vexing outcome of organ transplantation, has been attributed by some to activation and by others to apoptosis of endothelial cells in the graft. We asked which of these processes causes acute vascular rejection by tracing the processes during the development of acute vascular rejection in porcine cardiac xenografts performed in baboons. Apoptosis, assayed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL), expression of activated caspase-3, and proapoptotic genes Bax and Bcl-x(L), was not detected until acute vascular rejection was well advanced, and even then, apoptosis was largely confined to myocytes. Activation of the endothelium, as evidenced by expansion of rough endoplasmic reticulum and increased ribosomal antigen and phospho-p70 S6 kinase, occurred early in the course of acute vascular rejection and progressed through the disease process. These findings suggest that acute vascular rejection is caused by an active metabolic process and not by apoptosis in the endothelium.
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PMID:Apoptosis and cellular activation in the pathogenesis of acute vascular rejection. 1248 Aug 7

Inosine 5'-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme that catalyzes the conversion of IMP to xanthosine monophosphate (XMP) at the branch point of purine nucleotide biosynthesis, leading to the generation of guanine nucleotides. Inhibition of IMPDH results in the depletion of guanine nucleotides, prevents cell growth by G1 arrest, and induces cell differentiation in a cell-type-specific manner. The molecular and sensing mechanisms underlying these effects are not clear. We have examined the induction of apoptosis by mycophenolic acid (MPA), a specific IMPDH inhibitor, in interleukin-3 (IL-3)-dependent murine hematopoietic cell lines. MPA treatment, at clinically relevant doses, caused apoptosis in 32D myeloid cells and in FL5.12 and BaF3 pre-B cells in the ongoing presence of IL-3. Apoptosis was completely prevented by the addition of guanosine at time points up to 12 hours, after which caspase 3 activity increased and apoptosis was not reversible. MPA treatment caused marked down-regulation of the MAP kinase kinase/extracellular regulatory kinase (MEK/Erk) pathway at 3 hours while simultaneously increasing the phosphorylation of c-Jun kinase. In addition, MPA strongly down-regulated the mammalian target of rapamcyin (mTOR) pathway, as indicated by the decreased phosphorylation of p70 S6 kinase and of 4EBP1. Inhibition of either the mitogen-activated protein kinase (MAPK) or the mTOR pathway alone by standard pharmacologic inhibitors did not induce apoptosis in IL-3-dependent cells, whereas inhibition of both pathways simulated the effects of MPA treatment. These results indicate that IMPDH inhibitors may be effective in modulating signal transduction pathways in hematopoietic cells, suggesting their usefulness in chemotherapeutic regimens for hematologic malignancies.
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PMID:Induction of apoptosis in IL-3-dependent hematopoietic cell lines by guanine nucleotide depletion. 1260 35

Fibroblast growth factor-2 (FGF-2) is an important molecule that controls bone formation through activation of osteoblastic cell replication and differentiation. The role of FGF-2 on human osteoblast survival and the signaling pathway that mediates its effect are not known. We studied the effect of FGF-2 on apoptosis induced by low serum concentration and the signal transduction pathway involved in this effect in human primary calvaria osteoblasts and immortalized osteoblastic cells. Treatment with FGF-2 for 24-48 h protected against osteoblast apoptosis induced by low serum concentration, through specific inhibition of caspase-2 and caspase-3 activity. Pharmacological inhibition of MEK-1 and p38 MAPK had no effect on the inhibition of caspases-2 and -3 induced by FGF-2. In contrast, inhibition of PI3K with LY294002 abolished the FGF-2-induced inhibition of caspases-2 and -3. FGF-2 increased PI3K activity but did not induce phosphorylation of Akt or the downstream effector p70 S6 kinase. FGF-2 also induced GSK-3alpha and beta phosphorylation in osteoblastic cells, which however did not result in beta-catenin accumulation or Lef/Tcf transcriptional activity. In contrast, lithium induced beta-catenin accumulation, Lef/Tcf transcriptional activation and increased caspase-2 and -3 activity. The results indicate that the immediate protective effect of FGF-2 on human osteoblastic cell apoptosis involves PI3K and inhibition of downstream caspases, independently of GSK-3 and beta-catenin-Lef/Tcf-mediated transcription.
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PMID:Fibroblast growth factor-2 induces osteoblast survival through a phosphatidylinositol 3-kinase-dependent, -beta-catenin-independent signaling pathway. 1519 39

Honokiol is a naturally occurring neolignan abundant in Magnoliae Cortex and has showed anti-proliferative and pro-apoptotic effects in a wide range of human cancer cells. However, the molecular mechanisms on the anti-proliferative activity in cancer cells have been poorly elucidated. In this study, we evaluated the growth inhibitory activity of honokiol in cultured estrogen receptor (ER)-negative MDA-MB-231 human breast cancer cells. Honokiol exerted anti-proliferative activity with the cell cycle arrest at the G0/G1 phase and sequential induction of apoptotic cell death in a concentration-dependent manner. The honokiol-induced cell cycle arrest was well correlated with the suppressive expression of CDK4, cyclin D1, CDK2, cyclin E, c-Myc, and phosphorylated retinoblastoma protein (pRb) at Ser780. Apoptosis caused by honokiol was also concomitant with the cleavage of caspases (caspase-3, -8, and -9) and Bid along with the suppressive expression of Bcl-2, but it was independent on the expression of Bax and p53. In addition, honokiol-treated cells exhibited the cleavage of poly (ADP-ribose) polymerase (PARP) and DNA fragmentation. In the analysis of signal transduction pathway, honokiol down-regulated the expression and phosphorylation of c-Src, epidermal growth factor receptor (EGFR), and Akt, and consequently led to the inactivation of mTOR and its downstream signal molecules including 4E-binding protein (4E-BP) and p70 S6 kinase. These findings suggest that honokiol-mediated inhibitory activity of cancer cell growth might be related with the cell cycle arrest and induction of apoptosis via modulating signal transduction pathways.
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PMID:Down-regulation of c-Src/EGFR-mediated signaling activation is involved in the honokiol-induced cell cycle arrest and apoptosis in MDA-MB-231 human breast cancer cells. 1913 78


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