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

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

The retinoblastoma tumor suppressor protein (RB) has been shown to play a role in regulating the eukaryotic cell cycle, promoting cellular differentiation, and modulating programmed cell death. Although regulation of RB tumor suppressor activity is mediated by reversible phosphorylation, an additional posttranslational modification involves the cleavage of 42 residues from the carboxy terminus of RB during the onset of drug-induced or receptor-mediated apoptosis. We now demonstrate that a recombinant p100cl RB species localizes to the nucleus where it may retain wildtype "pocket" protein binding activity. In addition, using immunocytochemistry, we show that cleavage of the endogenous RB protein occurs in vivo in human cells and that p100cl is predominantly retained within the nuclear compartment of cells during early apoptosis. We also show that the carboxy-terminal cleavage of RB is detected immediately following caspase-3 and PARP cleavage during FAS-mediated apoptosis of MCF10 cells. These findings suggest that this cleavage event may be a component of a downstream cascade during programmed cell death.
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PMID:The 100-kDa proteolytic fragment of RB is retained predominantly within the nuclear compartment of apoptotic cells. 1042 29

MDM2 is a substrate of caspase-3 in p53-mediated apoptosis. In addition, MDM2 mediates its own ubiquitination in a RING finger-dependent manner. Thus, we investigated whether MDM2 is degraded through a ubiquitin-dependent proteasome pathway in the absence of p53. When HL-60 cells, p53 null, were treated with etoposide, MDM2 was markedly decreased prior to caspase-3-dependent retinoblastoma tumor suppressor protein (pRb) and poly (ADP- ribose) polymerase (PARP) cleavages. Moreover, down-regulation of MDM2 level was not coupled with its mRNA down-regulation. However, the level of MDM2 was partially restored by proteasome inhibitors such as LLnL and lactacystin, even in the presence of etoposide. Our results suggest that, in the p53 null status, MDM2 protein level is decreased by proteasome-mediated proteolysis prior to caspase-3-dependent PARP and pRb cleavages.
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PMID:The levels of MDM2 protein are decreased by a proteasome-mediated proteolysis prior to caspase-3-dependent pRb and PARP cleavages. 1130 36

The retinoblastoma tumor suppressor protein, pRb, is a key regulator of cell cycle and has been implicated in the terminal differentiation of neuronal cells. Mice nullizygous for pRb die by embryonic day 14.5 from hematopoietic and neurological defects attributed to failed differentiation (Clarke et al., 1992; Jacks et al., 1992; Lee et al., 1992). Previous studies by MacLeod et al. (1996) have demonstrated that the loss of p53 protects Rb-deficient CNS neurons but not peripheral nervous system (PNS) neurons from cell death. Thus, the mechanisms by which PNS neurons undergo apoptosis in response to Rb deficiency remain unknown. In view of the pivotal role of caspase 3 in the regulation of neuronal apoptosis during development, we examined its function in the execution of the wide-spread neuronal cell death induced by Rb deficiency. Our results support a number of conclusions. First, we show that caspase 3 becomes activated in all neuronal populations undergoing apoptosis. Second, caspase 3 deficiency does not extend the life span of Rb null embryos, because double null mutants exhibit high rates of liver apoptosis resulting in erythropoietic failure. Third, Rb/caspase 3 double-mutant neurons of the CNS exhibit widespread apoptosis similar to that seen in Rb mutants alone; thus caspase 3 deficiency does not protect this population from apoptosis. Finally, in contrast to the CNS, neurons of the PNS including those comprising the trigeminal ganglia and the dorsal root ganglia are protected from apoptosis in Rb/caspase 3 double-mutant embryos. Examination of the mechanistic differences between these two cell types suggest that CNS neurons may invoke other caspases to facilitate apoptosis in the absence of caspase 3. These findings suggest that PNS neurons are dependent on caspase 3 for the execution of apoptosis and that caspase 3 may serve as a key therapeutic target for neuroprotection after injury of this cell type.
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PMID:Caspase 3 deficiency rescues peripheral nervous system defect in retinoblastoma nullizygous mice. 1154 19

Prior studies have shown that cyclooxygenase (COX)-2, an enzyme involved in inflammatory mechanisms as well as neuronal activities, is up-regulated in the Alzheimer's disease (AD) brain and may represent a therapeutic target for anti-inflammatory treatments. We report the effect of neuronal overexpression of human (h)COX-2 in a murine model of AD neuropathology. Transgenic mice expressing both the human amyloid precursor protein mutation (APPswe) and the human presenilin (PS1-A246E) mutation, with resultant AD plaque pathology, were crossed with transgenic mice expressing human (h)COX-2 in neurons. At 12 months of age, the APPswe/PS1-A246E/hCOX-2 triple-transgenic mice showed an elevation in the number of phosphorylated retinoblastoma (pRb) tumor suppressor protein and active caspase-3 immunopositive neurons, compared to double APPswe/PS1-A246E or single hCOX-2 transgenic controls. No detectable influence of neuronal hCOX-2 on AD neuropathology was found in the brain of APPswe/PS1-A246E/hCOX-2 triple-transgenic mice, compared to double APPswe/PS1-A246E. In vitro studies revealed that hCOX-2 overexpression in primary cortico-hippocampal neurons derived from the hCOX-2 transgenics accelerates beta-amyloid (Abeta)(1-42)-mediated apoptotic damage which was prevented by the cell cycle dependent (CDK) inhibitor, flavoperidol. The data indicates that COX-2 overexpression causes alteration of neuronal cell cycle in a murine model of AD neuropathology, and provides a rational basis for targeting neuronal COX-2 in therapeutic research aimed at slowing the clinical progression of AD.
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PMID:Cyclooxygenase (COX)-2 and cell cycle activity in a transgenic mouse model of Alzheimer's disease neuropathology. 1195 94

Phosphatidylinositol (PI) 3-kinase signaling regulates numerous cellular processes, including proliferation, migration, and survival, which are required for neointimal hyperplasia and restenosis. The effectors of PI 3-kinase are activated by the phospholipid products of PI 3-kinase. In this report, we investigated the hypothesis that overexpression of the tumor suppressor protein PTEN, an inositol phosphatase specific for the products of PI 3-kinase, would inhibit the vascular smooth muscle cell (VSMC) responses necessary for neointimal hyperplasia and restenosis. Effects of PTEN were assessed in primary rabbit VSMCs after overexpression with a recombinant adenovirus and compared with uninfected or control virus-infected cells. PTEN was expressed endogenously in VSMCs, and PTEN overexpression inhibited PDGF-induced phosphorylation of p70(s6k), Akt, and glycogen synthase kinase-3-alpha and -beta but not ERK1 or -2. Overexpression of PTEN significantly inhibited both basal and PDGF-mediated VSMC proliferation and migration, the latter possibly due in part to downregulation of focal adhesion kinase. Moreover, PTEN overexpression induced cleavage of caspase-3 and significantly increased apoptosis compared with control cells. Taken together, these results demonstrate that PTEN overexpression potently inhibits the VSMC responses required for neointimal hyperplasia and restenosis. Adenovirus-expressed PTEN may therefore provide a useful tool for the local treatment of these and other vascular proliferative disorders.
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PMID:Inhibition of vascular smooth muscle cell proliferation, migration, and survival by the tumor suppressor protein PTEN. 1200 81

Necdin is expressed predominantly in postmitotic neurons and serves as a growth suppressor that is functionally similar to the retinoblastoma tumor suppressor protein. Using primary cultures of dorsal root ganglion (DRG) of mouse embryos, we investigated the involvement of necdin in the terminal differentiation of neurons. DRG cells were prepared from mouse embryos at 12.5 days of gestation and cultured in the presence of nerve growth factor (NGF). Immunocytochemistry revealed that necdin accumulated in the nucleus of differentiated neurons that showed neurite extension and expressed the neuronal markers microtubule-associated protein 2 and synaptophysin. Suppression of necdin expression in DRG cultures treated with antisense oligonucleotides led to a marked reduction in the number of terminally differentiated neurons. The antisense oligonucleotide-treated cells did not attempt to reenter the cell cycle, but underwent death with characteristics of apoptosis such as caspase-3 activation, nuclear condensation, and chromosomal DNA fragmentation. Furthermore, a caspase-3 inhibitor rescued antisense oligonucleotide-treated cells from apoptosis and significantly increased the population of terminally differentiated neurons. These results suggest that necdin mediates the terminal differentiation and survival of NGF-dependent DRG neurons and that necdin-deficient nascent neurons are destined to caspase-3-dependent apoptosis.
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PMID:Necdin is required for terminal differentiation and survival of primary dorsal root ganglion neurons. 1208 4

Free fatty acids (FFA) have been reported to reduce pancreatic beta-cell mitogenesis and to increase apoptosis. Here we show that the FFA, oleic acid, increased apoptosis 16-fold in the pancreatic beta-cell line, INS-1, over a 18-h period as assessed by Hoechst 33342/propidium iodide staining and caspase-3 and -9 activation, with negligible necrosis. A parallel analysis of the phosphorylation activation of protein kinase B (PKB) showed this was reduced in the presence of FFA that correlated with the incidence of apoptosis. At stimulatory 15 mm glucose and/or in the added presence of insulin-like growth factor 1, FFA-induced beta-cell apoptosis was lessened compared with that at a basal 5 mm glucose. However, most strikingly, adenoviral mediated expression of a constitutively active PKB, but not a "kinase-dead" PKB variant, essentially prevented FFA-induced beta-cell apoptosis under all glucose/insulin-like growth factor 1 conditions. Further analysis of pro-apoptotic downstream targets of PKB, implicated a role for PKB-mediated phosphorylation inhibition of glycogen synthase kinase-3alpha/beta and the forkhead transcription factor, FoxO1, in protection of FFA-induced beta-cell apoptosis. In addition, down-regulation of the pro-apoptotic tumor suppressor protein, p53, via PKB-mediated phosphorylation of MDM2 might also play a role in partially protecting beta-cells from FFA-induced apoptosis. Adenoviral mediated expression of wild type p53 potentiated FFA-induced beta-cell apoptosis, whereas expression of a dominant negative p53 partly inhibited beta-cell apoptosis by approximately 50%. Hence, these data demonstrate that PKB activation plays an important role in promoting pancreatic beta-cell survival in part via inhibition of the pro-apoptotic proteins glycogen synthase kinase-3alpha/beta, FoxO1, and p53. This, in turn, provides novel insight into the mechanisms involved in FFA-induced beta-cell apoptosis.
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PMID:Protein kinase B/Akt prevents fatty acid-induced apoptosis in pancreatic beta-cells (INS-1). 1239 70

Cisplatin, a commonly used antineoplastic agent, destroys the sensory hair cells in the cochlear and vestibular system leading to irreversible hearing loss and balance problems. Cisplatin-induced hair cell damage presumably occurs by apoptosis. Recent studies suggest that p53 may play an important role initiating cisplatin-induced apoptosis in some cell types. To determine if p53 plays a role in cisplatin-mediated hair cell loss, cochlear and utricular organotypic cultures were prepared from postnatal day 3-4 rats and treated with cisplatin or cisplatin plus pifithrin-alpha (PFT), a p53 inhibitor. Control cultures were devoid of p53 immunolabeling, caspase-1 and caspase-3 labeling and p53 protein was absent from Western blots. Cisplatin (1-10 microg/ml) caused a dose-dependent loss of hair cells in cochlear and utricular cultures, up-regulated phospho-p53 serine 15 immunolabeling, increased the expression of phospho-p53 serine 15 in Western blots from 6 to 48 h after the onset of cisplatin-treatment, and increased caspase-1 and caspase-3 labeling in cochlear and vestibular cultures. Addition of PFT (20-100 microM) to cisplatin-treated cochlear and utricular cultures resulted in a dose-dependent increase in hair cell survival; suppressed the expression of p53 in Western blots and eliminated caspase-1 and caspase-3 labeling in cultures. These results suggest that the tumor suppressor protein, p53, plays a critical role in initiating apoptosis in cochlear and vestibular hair cells. Temporary suppression of p53 with PFT provides significant protection against cisplatin-induced hair cell loss and offers the potential for reducing the ototoxic, vestibulotoxic and neurotoxic side effects of cisplatin.
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PMID:Pifithrin-alpha suppresses p53 and protects cochlear and vestibular hair cells from cisplatin-induced apoptosis. 1284 52

Geldanamycin (GA) binds to heat shock protein 90 (Hsp90) and interferes with its function which is to protect various cellular proteins involved in signaling, growth control, and survival from ubiquitination and subsequent degradation by the proteasome. Recently, we demonstrated that GA inhibited migration of glioma cells in vitro associated with downregulation of hypoxia-inducible factor (HIF-1 alpha) and phosphorylation of focal adhesion kinase (FAK) (Zagzag et al., 2003, J Cell Physiol 196:394-402). Here, we have investigated the mechanisms through which GA treatment of the T98G glioma cell line induces apoptosis. We found that GA treatment induced cell death in a caspase-dependent manner through activation of caspase-3 and PARP cleavage together with release of cytochrome c and apoptosis inducing factor (AIF) from the mitochondria. Use of synchronized T98G cells showed that GA treatment of glioma cells during S-phase enhanced cytotoxicity followed by M-phase arrest, resulting in mitotic catastrophe. In addition, apoptosis was associated with the downregulation of the survival protein, phosphorylated Akt (pAkt), an important signaling protein in the PI3K pathway, that is overexpressed in many cancers including gliomas. Given that many glioma tumors show deregulation of the PI3K signaling pathway, either through loss of the tumor suppressor protein PTEN or overexpression of the growth factor EGFR, the ability to identify different subsets of patients using simple immunohistochemistry for the presence of absence of pAkt could enable selection of the appropriate kinase inhibitor, such as GA, for drug therapy. Based on our data presented here, GA or its analogs may have potential in the treatment of glioma.
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PMID:Geldanamycin induces mitotic catastrophe and subsequent apoptosis in human glioma cells. 1538 45

Silymarin, a plant flavonoid, has been shown to inhibit skin carcinogenesis in mice. However, the mechanism responsible for the anti-skin carcinogenic effects of silymarin is not clearly understood. Here, we report that treatment of JB6 C141 cells (preneoplastic epidermal keratinocytes) and p53+/+ fibroblasts with silymarin and silibinin (a major constituent of silymarin) resulted in a dose-dependent inhibition of cell viability and induction of apoptosis in an identical manner. Silymarin-induced apoptosis was determined by fluorescence staining (8-64% apoptosis) and flow cytometry (12-76% apoptosis). The silymarin-induced apoptosis was primarily p53 dependent because apoptosis occurred to a much greater extent in the cells expressing wild-type p53 (p53+/+, 9-61%) than in p53-deficient cells (p53-/-, 6-20%). The induction of apoptosis in JB6 C141 cells was associated with increased expression of the tumor suppressor protein, p53, and its phosphorylation at Ser15. The constitutive expression of antiapoptotic proteins Bcl-2 and Bcl-xl were decreased after silymarin treatment, whereas the expression of the proapoptotic protein Bax was increased. There was a shift in Bax/Bcl-2 ratio in favor of apoptotic signal in silymarin-treated cells, which resulted in increased levels of cytochrome c release, apoptotic protease-activating factor-1, and cleaved caspase-3 and poly(ADP-ribose) polymerase in JB6 C141 cells. The shift in Bax/Bcl-2 ratio was more prominent in p53+/+ fibroblasts than in p53-/- cells. Silymarin-induced apoptosis was blocked by the caspase inhibitor (Z-VAD-FMK) in JB6 C141 cells which suggested the role of caspase activation in the induction of apoptosis. These observations show that silymarin-induced apoptosis is primarily p53 dependent and mediated through the activation of caspase-3.
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PMID:Silymarin induces apoptosis primarily through a p53-dependent pathway involving Bcl-2/Bax, cytochrome c release, and caspase activation. 1571 92


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