Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated that IGFBP-5 production by mammary epithelial cells increases dramatically during involution of the mammary gland. To demonstrate a causal relationship between IGFBP-5 and cell death we created transgenic mice expressing IGFBP-5 in the mammary gland using a mammary-specific promoter, beta-lactoglobulin. DNA content in the mammary glands of transgenic mice was decreased as early as day 10 of pregnancy. Histological analysis indicated reduced numbers of alveolar end buds, with decreased ductal branching. Transgenic dams produced IGFBP-5 in their milk at concentrations similar to those achieved at the end of normal lactation. Mammary cell number and milk synthesis were both decreased by approximately 50% during the first 10 days of lactation. BrdU labelling was decreased, whereas DNA ladders were increased in transgenic animals on day 1 of lactation. On day 2 postpartum, the epithelial invasion of the mammary fat pad was clearly impaired in transgenic animals. The concentrations of the pro-apoptotic molecule caspase-3 and of plasmin were both increased in transgenic animals whilst the concentrations of 2 prosurvival molecules Bcl-2 and Bcl-x(L)were both decreased. In order to examine whether IGFBP-5 acts by inhibiting the survival effect of IGF-I we examined IGF receptor phosphorylation and Akt phosphorylation and showed that both were inhibited. We attempted to "rescue" the transgenic phenotype by using growth hormone to increase endogenous IGF-I concentrations or by implanting minipumps delivering an IGF-1 analogue, R(3)-IGF-1, which binds weakly to IGFBP-5. Growth hormone treatment failed to affect mammary development suggesting that increased concentrations of endogenous IGF-1 are insufficient to overcome the high concentrations of IGFBP-5 produced by these transgenic animals. In contrast mammary development (gland weight and DNA content) was normalised by R3-IGF-I although milk production was only partially restored. This is the first demonstration that over-expression of IGFBP-5 can lead to; impaired mammary development, increased expression of the pro-apoptotic molecule caspase-3, increased plasmin generation and decreased expression of pro-survival molecules of the Bcl-2 family. It clearly demonstrates that IGF-I is an important developmental/survival factor for the mammary gland and, furthermore, this cell death programme may be utilised in a wide variety of tissues.
...
PMID:Insulin-like growth factor binding protein-5 (IGFBP-5) induces premature cell death in the mammary glands of transgenic mice. 1222 11

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.
...
PMID:TSH signaling and cell survival in 3T3-L1 preadipocytes. 1222 69

Macrophage colony-stimulating factor (M-CSF) is known as one of the factors essential for osteoclast development. In the present study, we examined effects of M-CSF on the apoptotic pathway of osteoclast precursors and their underlying molecular mechanisms. Osteoclast precursors underwent apoptosis in the absence of M-CSF, even in the presence of receptor activator of NF-kappakB ligand (RANKL). Active caspase-3 and -9 were detected in the osteoclast precursors and treatments of precursors with their specific inhibitors (Z-DEVD-FMK and Z-LEHD-FMK) decreased the apoptosis. M-CSF decreased apoptosis in a dose-dependent manner with decreasing in active caspases-3 and -9 levels and up-regulating Bcl-X(L). Those effects of M-CSF on inhibiting apoptosis of osteoclasts precursor by regulating anti-apoptotic signals was more effective when combined with RANKL. These results demonstrate that M-CSF acts as a survival factor for the osteoclast precursors. Furthermore, it is believed that the apoptosis of osteoclast precursors may be involved in the activation of caspase-9 and that M-CSF may promote their survival through Bcl-X(L)-induced inhibition of caspase-9 activation.
...
PMID:Macrophage colony-stimulating factor promotes the survival of osteoclast precursors by up-regulating Bcl-X(L). 1252 97

Green tea polyphenols (catechins) are known to induce cell death in many types of tumor cells, but how normal epithelial cells survive in the presence of polyphenols is unknown. We recently reported that green tea polyphenols potently induced a cyclin-dependent kinase inhibitor, p57/(KIP2), only in normal human epithelial cells. In this study, we investigated the correlation between p57 expression and survival/apoptosis by Western blot analysis, caspase 3 assays and morphological analysis. It was demonstrated that, in the cells that lack p57 induction, green tea polyphenols induced Apaf-1 expression along with caspase 3 activation, leading to apoptosis. In contrast, cells with polyphenol-inducible p57 maintained constant levels of Apaf-1 and proliferating cell nuclear antigen (PCNA), with basal caspase 3 activity. Retroviral-transfected, p57-expressing oral carcinoma cells showed significant resistance to green tea polyphenol-induced apoptosis. Our results suggest that p57/KIP2 is a determinant pro-survival factor for cell protection from green tea polyphenol-induced apoptosis.
...
PMID:Induction of p57 is required for cell survival when exposed to green tea polyphenols. 1255 41

Activated protein C (APC) is a systemic anti-coagulant and anti-inflammatory factor. It reduces organ damage in animal models of sepsis, ischemic injury and stroke and substantially reduces mortality in patients with severe sepsis. It was not known whether APC acts as a direct cell survival factor or whether its neuroprotective effect is secondary to its anti-coagulant and anti-inflammatory effects. We report that APC directly prevents apoptosis in hypoxic human brain endothelium through transcriptionally dependent inhibition of tumor suppressor protein p53, normalization of the pro-apoptotic Bax/Bcl-2 ratio and reduction of caspase-3 signaling. These mechanisms are distinct from those involving upregulation of the genes encoding the anti-apoptotic Bcl-2 homolog A1 and inhibitor of apoptosis protein-1 (IAP-1) by APC in umbilical vein endothelial cells. Cytoprotection of brain endothelium by APC in vitro required endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR-1), as did its in vivo neuroprotective activity in a stroke model of mice with a severe deficiency of EPCR. This is consistent with work showing the direct effects of APC on cultured cells via EPCR and PAR-1 (ref. 9). Moreover, the in vivo neuroprotective effects of low-dose mouse APC seemed to be independent of its anti-coagulant activity. Thus, APC protects the brain from ischemic injury by acting directly on brain cells.
...
PMID:Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. 1261 68

Limited proliferative capacity is a characteristic of most normal human cells and results in a growth-arrested state, called replicative senescence. Functional expression of the telomerase catalytic subunit (human telomerase reverse transcriptase; hTERT) in human activated hepatic stellate cells (HSCs) rescues them from death with immortalization and maintains an activated HSC phenotype. The aim of this study was to evaluate alterations in gene and protein expression of in vitro aged human activated HSCs and to define the pathway by which senescent-activated HSCs are eliminated in culture. Altered patterns of gene expression in senescent human HSCs were assessed using DNA microarray analysis and compared with early passage HSCs or hTERT immortalized HSCs. Senescent HSCs showed higher expression of inflammation and stress-associated genes as compared with early passage HSCs. Senescent HSCs expressed reduced levels of extracellular matrix proteins, including collagens, tenascin, and fibronectin. TUNEL staining of senescent HSCs showed approximately 21% positive cells, indicating DNA fragmentation and apoptosis. Apoptosis involved the mitochondrial pathway with decreased levels of Bcl-2 and Bcl-x(L) protein, release of cytochrome c, and increased caspase-3 activity. In contrast, 4% to 5% of early activated HSCs or telomerase positive HSCs were TUNEL positive. In conclusion, cultured human HSCs undergo a switch from a fibrogenic to an inflammatory phenotype, suggesting that senescent human HSCs might modulate chronic wound healing processes. Maintenance of telomere length represents an important survival factor for activated human HSCs.
...
PMID:Replicative senescence of activated human hepatic stellate cells is accompanied by a pronounced inflammatory but less fibrogenic phenotype. 1260 63

High levels of cytokines are associated with a poor prognosis in acute myeloid leukemia (AML). However, cytokines may induce, on one hand, survival factor expression and cell proliferation and, on the other hand, expression of inhibitory signals such as up-regulation of suppressors of cytokine signaling (SOCS) and induce apoptotic cell death. Because blasts from patients with AML express high procaspase protein levels, we asked whether granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances procaspase protein production in AML cells. In the GM-CSF-responsive OCIM2 AML cell line, GM-CSF induced signal transducer and activator of transcription 5 (Stat 5) phosphorylation, up-regulated cyclin D2, and stimulated cell cycle progression. Concurrently, GM-CSF stimulated expression of SOCS-2 and -3 and of procaspases 2 and 3 and induced caspase 3 activation, poly(ADP[adenosine 5'-diphosphate]-ribose) polymerase (PARP) cleavage, and apoptotic cell death. The Janus kinase (Jak)-Stat inhibitor AG490 abrogated GM-CSF-induced expression of procaspase 3 and activation of caspase 3. Under the same conditions GM-CSF up-regulated production of BAX as well as Bcl-2, Bcl-XL, survivin, and XIAP. GM-CSF also increased procaspase 3 protein levels in OCI/AML3 and Mo7e cells, suggesting that this phenomenon is not restricted to a single leukemia cell line. Our data suggest that GM-CSF exerts a dual effect: it stimulates cell division but contemporaneously up-regulates Jak-Stat-dependent proapoptotic proteins. Up-regulation of procaspase levels in AML is thus a beacon for an ongoing growth-stimulatory signal.
...
PMID:Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces antiapoptotic and proapoptotic signals in acute myeloid leukemia. 1266 43

We have used expression of a kinase dead mutant of PKCalpha (PKCalphaKD) to explore the role of this isoform in salivary epithelial cell apoptosis. Expression of PKCalphaKD by adenovirus-mediated transduction results in a dose-dependent induction of apoptosis in salivary epithelial cells as measured by the accumulation of sub-G1 DNA, activation of caspase-3, and cleavage of PKCdelta and PKCzeta, known caspase substrates. Induction of apoptosis is accompanied by nine-fold activation of c-Jun-N-terminal kinase, and an approximately two to three-fold increase in activated mitogen-activated protein kinase (MAPK) as well as total MAPK protein. Previous studies from our laboratory have shown that PKCdelta activity is essential for the apoptotic response of salivary epithelial cells to a variety of cell toxins. To explore the contribution of PKCdelta to PKCalphaKD-induced apoptosis, salivary epithelial cells were cotransduced with PKCalphaKD and PKCdeltaKD expression vectors. Inhibition of endogenous PKCdelta blocked the ability of PKCalphaKD to induce apoptosis as indicated by cell morphology, DNA fragmentation, and caspase-3 activation, indicating that PKCdelta activity is required for the apoptotic program induced under conditions where PKCalpha is inhibited. These findings indicate that PKCalpha functions as a survival factor in salivary epithelial cells, while PKCdelta functions to regulate entry into the apoptotic pathway.
...
PMID:Inhibition of PKCalpha induces a PKCdelta-dependent apoptotic program in salivary epithelial cells. 1270 Jun 27

Following activation with proliferative stimuli, including ligation of CD40, dense human tonsillar B cells (>98% cells in G(0)) have increased cleavage and activation of caspase-8 and -6 accompanied by decreased caspase-3 activation and apoptosis. Proliferation was blocked by either a broad specificity caspase inhibitor or inhibitors selective for caspase-6 or caspase-8. In contrast, an inhibitor selective for caspase-3 was without effect. Furthermore, induction of cyclin D and cyclin-dependent kinase 4 mRNA and protein was blocked upon inhibition of caspase-6, but not caspase-3. Thus, caspase-6-like activity is required for quiescent B cells to increase the expression of genes required for entry into G(1). In support of this model, the transcriptional suppressor special AT-rich sequence-binding protein 1, a preferred caspase-6 substrate, was cleaved upon B cell stimulation. Caspase activity was not required for all signaling events, as caspase inhibitors did not affect the phosphorylation of p42/44 mitogen-activated protein kinase, the expression of the survival factor cellular inhibitor of apoptosis 2, or the production of IL-6 by stimulated G(0) B cells. These findings suggest a mechanism by which caspase-6 may selectively allow entry of quiescent B cells into the cell cycle.
...
PMID:Caspase activity is required for stimulated B lymphocytes to enter the cell cycle. 1279 35

Autoantibodies against recoverin are found in the sera of patients with cancer-associated retinopathy syndrome, a paraneoplastic disease associated with retinal degeneration. We have previously shown that anti-recoverin autoantibodies induced photoreceptor apoptotic cell death after injection into the vitreous of Lewis rats. Ciliary neurotrophic factor (CNTF) has been shown to promote the survival of a number of neuronal cell types, including photoreceptors. In this study, we examined whether an adeno-associated virus (AAV)-mediated delivery of gene encoding the human CNTF protected photoreceptor cells from anti-recoverin antibody-induced death. One month after subretinal injection of the AAV-CNTF gene into one eye and a control vector into the other eye, an anti-recoverin antibody was injected to induce retinal cell death in Lewis rats. Subretinal administration of the virus led to an efficient transduction of photoreceptors, as indicated by immunostaining of retinas with anti-CNTF. Histological examination of the corresponding retinas showed that photoreceptor cells were significantly protected from apoptotic death in the CNTF-treated eyes. CNTF treatment of the retinas resulted in a time-dependent activation of STAT 3. The present study shows that an AAV-mediated delivery of CNTF may protect photoreceptors from antibody-induced cell death through the activation of STAT3 and the suppression of caspase 3 activity, a key caspase leading to apoptosis. Thus, CNTF may be a useful treatment for human antibody-mediated retinal degeneration.
...
PMID:Anti-apoptotic effects of CNTF gene transfer on photoreceptor degeneration in experimental antibody-induced retinopathy. 1293 81


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---