UNIPROT:P42574 - FACTA Search

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

Molecular and intra-cellular mechanisms involved in the regulation of apoptosis processes in endometrial cells are poorly understood and documented. We have investigated the possibility that Akt survival pathway might be involved in the regulation of apoptosis in the uterus during the estrous cycle. Rats with regular estrous cycle (4 days) were killed at different days of estrous cycle (diestrus, proestrus, estrus and metestrus). Uteri were collected and fixed for immunohistochemical staining (IHC) and apoptotic cell death detection by [TdT]-mediated deoxyuridinetriphosphate nick end-labelling (TUNEL) or endometrial protein extracts collected for Western analysis. TUNEL analysis revealed that apoptosis was mainly found at estrus compared to other day of estrous cycle. TUNEL positive cells were apparent in luminal epithelial cells only. No apoptotic cells were observed at proestrus. In contrast, proliferation was maximal at proestrus as confirmed with the expression of CDC47/MCM7 (a cell proliferation marker). Intact form of caspase-3 was maximal at proestrus and was reduced only at estrus. Likewise, presence of a specific cleaved caspase-3 fragment was observed only at estrus and IHC revealed that cleaved caspase-3 signal was found in luminal epithelial cells. PTEN protein, a phosphatase involved in the regulation of Akt phosphorylation, was present at all days of estrous cycle and showed no significant regulation in relation to cycle. Expression of phospho-Akt (the activated form of Akt) was present at metestrus, diestrus, and proestrus but decreased significantly at estrus. Akt protein expression was maximal at estrus. IHC revealed that Akt expression was high in both stromal and epithelial cells at estrus. Further studies using ovariectomized rats demonstrated that 17beta-estradiol increased endometrial cell proliferation which was accompanied by an increase of both Akt expression and phosphorylation. These results suggest that increased Akt expression and activity in response to estradiol may be an important mechanism to protect endometrial cells from apoptotic triggering and to induce endometrial cell proliferation, whereas inhibition of Akt activity leads to caspase-3 activation and apoptosis in endometrial cells.
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PMID:Regulation of Akt expression and phosphorylation by 17beta-estradiol in the rat uterus during estrous cycle. 1281 42

The cytokine interleukin-16 is generated by posttranscriptional cleavage by caspase-3 of two large precursor isoforms. The smaller protein of 67 kDa (pro-IL-16) is expressed in cells of the immune system and contains three PDZ (postsynaptic density/disc large/zona occludens-1) domains, whereas the larger 141-kDa neuronal variant (npro-IL-16) has two additional PDZ domains in its N-terminal extension that interact with neuronal ion channels. Using the yeast two-hybrid approach we have identified three closely related myosin phosphatase targeting subunits, MYPT1, MYPT2, and MBS85, as binding partners of the IL-16 precursor proteins. These interactions were verified using pull-down assays, coimmunoprecipitations, and plasmon resonance experiments. Binding requires the intact PDZ2 domain of pro-IL-16 and highly related C-terminal regions in the ligands consisting of a short leucine zipper and an indispensable serine at the -1 position, suggesting a novel unconventional PDZ binding mode. Pro-IL-16 and the myosin phosphatase targeting subunits colocalize along actomyosin filaments and stress fibers in transfected COS-7 cells. By modulating and targeting the catalytic phosphatase subunit to its substrates, MYPT1, MYPT2, and MBS85 regulate various contractile processes in muscle and non-muscle cells. Our findings indicate an involvement of the IL-16 precursor molecules in myosin-based contractile processes, most likely in cell motility, providing a functional link to the chemotactic activity of the mature cytokine. Alternatively, an intracellular complex of npro-IL-16, ion channels, and components of myosin motors in neurons suggests a role in protein targeting.
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PMID:PDZ Domain-mediated interaction of interleukin-16 precursor proteins with myosin phosphatase targeting subunits. 1292 70

Protein phosphatase-directed toxins such as okadaic acid (OA) are general apoptosis inducers. We show that a protein (inhibitor of radiation- and OA-induced apoptosis, Irod/Ian5), belonging to the family of immune-associated nucleotide binding proteins, protected Jurkat T-cells against OA- and gamma-radiation-induced apoptosis. Unlike previously described antiapoptotic proteins Irod/Ian5 did not protect against anti-Fas, tumor necrosis factor-alpha, staurosporine, UV-light, or a number of chemotherapeutic drugs. Irod antagonized a calmodulin-dependent protein kinase II-dependent step upstream of activation of caspase 3. Irod has predicted GTP-binding, coiled-coil, and membrane binding domains. Irod localized to the centrosomal/Golgi/endoplasmic reticulum compartment. Deletion of either the C-terminal membrane binding domain or the N-terminal GTP-binding domain did not affect the antiapoptotic function of Irod, nor the centrosomal localization. The middle part of Irod, containing the coiled-coil domain, was therefore responsible for centrosomal anchoring and resistance toward death. Being widely expressed and able to protect also nonimmune cells, the function of Irod may not be limited to the immune system. The function and localization of Irod indicate that the centrosome and calmodulin-dependent protein kinase II may have important roles in apoptosis signaling.
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PMID:Irod/Ian5: an inhibitor of gamma-radiation- and okadaic acid-induced apoptosis. 1292 64

Chronic ethanol consumption can cause sustained hepatocellular injury and inhibit the subsequent regenerative response. These effects of ethanol may be mediated by impaired hepatocyte survival mechanisms. The present study examines the effects of ethanol on survival signaling in the intact liver. Adult Long Evans rats were maintained on ethanol-containing or isocaloric control liquid diets for 8 weeks, after which the livers were harvested to measure mRNA levels, protein expression, and kinase or phosphatase activity related to survival or proapoptosis mechanisms. Chronic ethanol exposure resulted in increased hepatocellular labeling for activated caspase 3 and nuclear DNA damage as demonstrated using the TUNEL assay. These effects of ethanol were associated with reduced levels of tyrosyl phosphorylated (PY) IRS-1 and PI3 kinase, Akt kinase, and Erk MAPK activities and increased levels of phosphatase tensin homologue deleted on chromosome 10 (PTEN) mRNA, protein, and phosphatase activity in liver tissue. In vitro experiments demonstrated that ethanol increases PTEN expression and function in hepatocytes. However, analysis of signaling cascade pertinent to PTEN function revealed increased levels of nuclear p53 and Fas receptor mRNA but without corresponding increases in GSK-3 activity or activated BAD. Although fork-head transcription factor levels were increased in ethanol-exposed livers, virtually all of the fork-head protein detected by Western blot analysis was localized within the cytosolic fraction. In conclusion, chronic ethanol exposure impairs survival mechanisms in the liver because of inhibition of signaling through PI3 kinase and Akt and increased levels of PTEN. However, uncoupling of the signaling cascade downstream of PTEN that mediates apoptosis may account for the relatively modest degrees of ongoing cell loss observed in livers of chronic ethanol-fed rats.
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PMID:Potential role of PTEN phosphatase in ethanol-impaired survival signaling in the liver. 1293 97

1. The Src homology protein tyrosine phosphatase SHP2 is associated with cytoskeletal maintenance, cell division, and cell differentiation, but the role of SHP2 during central nervous system injury requires further definition. We therefore characterized the role of SHP2 during nitric oxide (NO)-induced programmed cell death (PCD). 2. Employing primary hippocampal neurons from mice with a dominant negative SHP2 mutant to render the phosphatase site of the SHP2 protein biologically inactive, but functionally capable of binding substrate, neuronal injury was evaluated by trypan blue, DNA fragmentation, membrane phosphatidyl serine (PS) exposure, mitogen-activated protein (MAP) kinase phosphorylation, and cysteine protease activity. NO was administered through the NO generators SIN-1 (300 microM) or NOC-9 (300 microM). 3. Following NO exposure, neuronal survival decreased from 89 +/- 3% in untreated controls to 37 +/- 2% in wild-type neurons and to 21 +/- 4% in SHP2 mutant neurons. In sister cultures following NO exposure, this increased susceptibility to neuronal injury paralleled enhanced genomic DNA degradation and membrane PS exposure with PCD induction increasing in SHP2 mutant neurons by approximately 42% during specified time periods when compared to wild-type neurons. Interestingly, modulation of the MAP kinase p38 appears to represent an initial level of neuronal protection employed by SHP2. In addition, both the rate and degree of caspase 1- and caspase 3-like activities in SHP2 mutant neurons were significantly increased over a 24-h course when compared to wild-type neurons. Inhibition of caspase 1- and caspase 3-like activities reversed the progression of neuronal PCD, suggesting that inhibition of cysteine protease activity is a downstream mechanism for SHP2 to afford neuronal protection. 4. Our work supports the premise that the tyrosine phosphatase SHP2 plays a dominant role during NO-induced PCD and may offer a potential molecular "checkpoint" against neurodegenerative disease.
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PMID:The tyrosine phosphatase SHP2 modulates MAP kinase p38 and caspase 1 and 3 to foster neuronal survival. 1451 16

Vitamin K-related analogs induce growth inhibition via a cell cycle arrest through cdc25A phosphatase inhibition in various cancer cell lines. We report that 2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone (DDN), a naphthoquinone analog, induces mitochondria-dependent apoptosis in human promyelocytic leukemia HL-60 cells. DDN induced cytochrome c release, Bax translocation, cleavage of Bid and Bad, and activation of caspase-3, -8, -9 upon the induction of apoptosis. Cleavage of Bid, the caspase-8 substrate, was inhibited by the broad caspase inhibitor z-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk), whereas cytochrome c release was not affected, suggesting that activation of caspase-8 and subsequent Bid cleavage occur downstream of cytochrome c release. DDN inhibited the activation of Akt detected by decreasing level of phosphorylation. Overexpression of constitutively active Akt protected cells from DDN-induced apoptosis, while dominant negative Akt moderately enhanced cell death. Furthermore, Akt prevented release of cytochrome c and cleavage of Bad in DDN-treated HL-60 cells. Taken together, DDN-induced apoptosis is associated with mitochondrial signaling which involves cytochrome c release via a mechanism inhibited by Akt.
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PMID:Involvement of Akt in mitochondria-dependent apoptosis induced by a cdc25 phosphatase inhibitor naphthoquinone analog. 1464 18

Focal adhesion kinase (FAK) prevents apoptosis in many cell types. We have reported that tyrosine residues in FAK are dephosphorylated and FAK is degraded during mannitol-induced apoptosis in human neuroblastoma cells. Several studies suggest that FAK dephosphorylation and degradation are separate events. The current study defines the relationship between FAK dephosphorylation and degradation in neuroblastoma cells using okadaic acid (OA). OA, a serine phosphatase inhibitor, promotes serine/threonine phosphorylation, which in turn blocks tyrosine phosphorylation. OA induced focal adhesion loss, actin cytoskeleton disorganization, and cellular detachment, which corresponded to a loss of FAK Tyr397 phosphorylation. These changes preceded caspase-3 activation, Akt and MAP kinase activity loss, protein ubiquitination, and cellular apoptosis. Insulin-like growth factor-I prevented mannitol-induced, but not OA-induced, substrate detachment and FAK Tyr397 dephosphorylation, and the effects of OA on FAK Tyr397 phosphorylation were irreversible. The proteolytic degradation of FAK is temporally distinct from its tyrosine dephosphorylation, occurring when apoptotic pathways are already initiated and during a generalized destruction of signaling proteins. Therefore, agents resulting in the dephosphorylation of FAK may be beneficial for therapeutic treatment, irrespective of FAK protein levels, as this may result in apoptosis, which cannot be prevented by growth factor signaling.
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PMID:Degradation and dephosphorylation of focal adhesion kinase during okadaic acid-induced apoptosis in human neuroblastoma cells. 1467 Jan 78

The expression of c-jun, mitogen-activated protein kinase phosphatase-1 (mkp-1), caspase-3 and glial fibrillary acidic protein (gfap) was examined at 1, 3 and 7 days after cortical cold injury in rats by in situ hybridisation and immunocytochemistry. Alterations of gene expression were related to metabolic disturbances and delayed cell death, as revealed by cerebral protein synthesis autoradiography, ATP bioluminescence, pH fluorescence and terminal transferase biotinylated dUTP nick end labelling (TUNEL). Protein synthesis autoradiographies depicted sharply demarcated cortex lesions, which were almost congruent with areas exhibiting ATP depletion (lesion volume: 16.9+/-11.8 mm(3) after 7 days). Lesions were surrounded by a region of tissue alkalosis, which was most prominent 1 day after trauma. Delayed cell injury, as revealed by TUNEL, was noticed in a thin rim around the lesion border on day 1 (tissue volume: 1.7+/-0.8 mm(3)) and, to lesser extent, days 3 and 7 post-lesioning. However, only a small percentage of cells in this area were positive for activated caspase-3 protein. TUNEL(+) cells were further seen in the ventrobasal thalamus after 7 days. In the thalamus, the appearance of DNA-fragmented cells was closely accompanied by activated caspase-3 expression. In situ hybridisations revealed that cell injury both in the peri-lesion rim and ventrobasal thalamus was associated with increased c-jun and gfap, but not mkp-1 and caspase-3 mRNA levels. Gene responses were not confined to areas revealing irreversible cell death: mkp-1 mRNA was bilaterally upregulated in the lesion-remote entorhinal cortex, cingulate cortex and reticular thalamus at 7 days after trauma, and caspase-3 mRNA was slightly, but significantly downregulated in the entorhinal cortex after 3 and 7 days. Gfap mRNA was elevated in all regions exhibiting tissue alkalosis. Our data suggest that delayed cell injury after cortex trauma may be apoptotic in the ventrobasal thalamus, but not the peri-lesion rim. The dissociated responses of c-jun, mkp-1 and caspase-3 mRNAs may represent important factors influencing tissue viability.
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PMID:Expression of c-jun, mitogen-activated protein kinase phosphatase-1, caspase-3 and glial fibrillary acidic protein following cortical cold injury in rats: relationship to metabolic disturbances and delayed cell death. 1469 45

The p53 tumor suppressor gene product plays an important role in the regulation of apoptosis. Transforming growth factor beta1 (TGF-beta1)-induced apoptosis in hepatic cells is associated with reduced expression of the retinoblastoma protein (pRb) and subsequent E2F-1-activated expression of apoptosis-related genes. In this study, we explored the potential role of p53 in TGF-beta1-induced apoptosis. HuH-7 human hepatoma cells were either synchronized in G1, S and G2/M phases, or treated with 1 nM TGF-beta1. The results indicated that greater than 90% of the TGF-beta1-treated cells were arrested in G1 phase of the cell cycle. This was associated with enhanced p53 dephosphorylation and p21(Cip1/Waf1) expression, which coincided with decreased Cdk2, Cdk4, and cyclin E expression, compared with synchronized G1 cells. In addition, p53 dephosphorylation coincided with caspase-3 activation, and translocation of p21(Cip1/Waf1) and p27(Kip1) into the cytoplasm, all of which were suppressed by caspase inhibition of TGF-beta1-induced apoptosis. Finally, phosphatase inhibition and pRb overexpression partially inhibited p53-mediated apoptosis. In conclusion, the results demonstrated that TGF-beta1-induced p53 dephosphorylation is associated with caspase-3 activation, and cytosolic translocation of p21(Cip1/Waf1) and p27(Kip1), resulting in decreased expression of Cdks and cyclins. Further, p53 appears to mediate TGF-beta1-induced apoptosis downstream of the pRb/E2F-1 pathway.
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PMID:p53 dephosphorylation and p21(Cip1/Waf1) translocation correlate with caspase-3 activation in TGF-beta1-induced apoptosis of HuH-7 cells. 1500 18

The causes of sporadic Parkinson's disease (PD) are poorly understood. 6-Hydroxydopamine (6-OHDA), a PD mimetic, is widely used to model this neurodegenerative disorder in vitro and in vivo; however, the underlying mechanisms remain incompletely elucidated. We demonstrate here that 6-OHDA evoked endoplasmic reticulum (ER) stress, which was characterized by an up-regulation in the expression of GRP78 and GADD153 (Chop), cleavage of procaspase-12, and phosphorylation of eukaryotic initiation factor-2 alpha in a human dopaminergic neuronal cell line (SH-SY5Y) and cultured rat cerebellar granule neurons (CGNs). Glycogen synthase kinase-3 beta (GSK3beta) responds to ER stress, and its activity is regulated by phosphorylation. 6-OHDA significantly inhibited phosphorylation of GSK3beta at Ser9, whereas it induced hyperphosphorylation of Tyr216 with little effect on GSK3beta expression in SH-SY5Y cells and PC12 cells (a rat dopamine cell line), as well as CGNs. Furthermore, 6-OHDA decreased the expression of cyclin D1, a substrate of GSK3beta, and dephosphorylated Akt, the upstream signaling component of GSK3beta. Protein phosphatase 2A (PP2A), an ER stress-responsive phosphatase, was involved in 6-OHDA-induced GSK3beta dephosphorylation (Ser9). Blocking GSK3beta activity by selective inhibitors (lithium, TDZD-8, and L803-mts) prevented 6-OHDA-induced cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP), DNA fragmentations and cell death. With a tetracycline (Tet)-controlled TrkB inducible system, we demonstrated that activation of TrkB in SH-SY5Y cells alleviated 6-OHDA-induced GSK3beta dephosphorylation (Ser9) and ameliorated 6-OHDA neurotoxicity. TrkB activation also protected CGNs against 6-OHDA-induced damage. Although antioxidants also offered neuroprotection, they had little effect on 6-OHDA-induced GSK3beta activation. These results suggest that GSK3beta is a critical intermediate in pro-apoptotic signaling cascades that are associated with neurodegenerative diseases, thus providing a potential target site amenable to pharmacological intervention.
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PMID:Glycogen synthase kinase 3beta (GSK3beta) mediates 6-hydroxydopamine-induced neuronal death. 1513 87

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