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

P19 embryonal carcinoma (EC) cells undergo apoptosis during neuronal differentiation induced by all-trans retinoic acid (RA). Caspase-3-like proteases are activated and involved in the apoptosis of P19 EC cells during neuronal differentiation.1 Recently it has been shown that growth factor signals protect against apoptosis by phosphorylation of Bad. Phosphorylated Bad, an apoptotic member of the Bcl-2 family, cannot bind to Bcl-xL and results in Bcl-xL homodimer formation and subsequent antiapoptotic activity. In the present study, we demonstrate that this system is used generally to protect against apoptosis during neuronal differentiation. Bcl-xL inhibited the activation of caspase-3-like proteases. Basic fibroblast growth factor (bFGF) inhibited more than 90% of the caspase-3-like activity, inhibited processing of caspase-3 into its active form, and inhibited DNA fragmentation. bFGF activated phosphatidyl-inositol-3-kinase (PI3K) and stimulated the phosphorylation of Bad. Phosphorylation was inhibited by wortmannin, an inhibitor of PI3K and its downstream target Akt. Thus, Bad is a target of the FGF receptor-mediated signals involved in the protection against activation of caspase-3.
 ...
PMID:bFGF inhibits the activation of caspase-3 and apoptosis of P19 embryonal carcinoma cells during neuronal differentiation. 1038 33

Forced overexpression of wild-type Alzheimer amyloid precursor protein (APP) causes postmitotic neurons to degenerate. Caspase-3 (CPP32) is a principal cell death protease involved in neuronal apoptosis during physiological development and under pathological conditions. Here, we investigated whether APP overexpression activates caspase-3 in human postmitotic neurons using adenovirus-mediated gene transfer. When a recombinant adenovirus vector expressing human wild-type APP695 was infected in vitro into neurally differentiated embryonal carcinoma NT2 cells, only postmitotic neurons underwent severe degeneration. Before neurodegeneration, full-length APP- and Abeta-immunoreactive peptides were accumulated in infected neurons, and caspase-3-like protease activity was markedly elevated. Western blot analysis revealed that activated caspase-3 subunits were generated in APP-accumulating neurons. Such neuronal caspase-3 activation was undetectable in NT2 neurons infected with beta-galactosidase-expressing adenovirus. Addition of the caspase-3 inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde to the culture medium significantly reduced the severity of degeneration exhibited by APP-overexpressing neurons. Immunocytochemical analyses revealed that some APP-accumulating neurons contained activated caspase-3 subunits and exhibited the characteristics of apoptosis, such as chromatin condensation and DNA fragmentation. Activation of caspase-3 was also observed in vivo in rat hippocampal neurons infected with the APP-expressing adenovirus. These results suggest that wild-type APP is an intrinsic activator of caspase-3-mediated death machinery in postmitotic neurons.
 ...
PMID:Activation of neuronal caspase-3 by intracellular accumulation of wild-type Alzheimer amyloid precursor protein. 1043 52

Caspase-9 is one caspase upstream of caspase-3 and its activation is stimulated by Apaf-1/cytochrome c and inhibited by Akt signals. BAD phosphorylation by Akt is an essential step for growth factor-mediated inhibition of caspase activation. Recently, it was shown that human caspase-9 is phosphorylated by Akt and that its protease activity is reduced. To clarify the molecular mechanism of regulation of caspase-9 activation in neuronal apoptosis, we isolated two alternative splicing products of mouse caspase-9, caspase-9L and caspase-9S, from a P19 embryonal carcinoma cell cDNA library. Curiously, the Akt phosphorylation sites and motifs found in human caspase-9 were absent in both mouse caspase-9L and -9S. Mouse caspase-9 was not phosphorylated by activated Akt in vitro. Reverse transcription polymerase chain reaction analysis showed that the absent Akt motif is not limited to caspase-9 expressed in P19 embryonal carcinoma cells but also occurs in caspase-9 expressed in mouse, rat, and monkey. These results suggest that inhibition of caspase-9 activation by Akt-dependent phosphorylation is not generalized across species.
 ...
PMID:Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9. 1052

Adeno-associated virus (AAV) type 2 Rep78 is a multifunctional protein required for AAV DNA replication, integration, and gene regulation. The biochemical activities of Rep78 have been described, but the effects of Rep proteins on the cell have not been characterized. We have analyzed Rep-mediated cytotoxicity. We demonstrated that Rep78 expression is sufficient to induce cell death and disruption of the cell cycle. Cell death was found to be mediated by apoptosis. Rep78 expression resulted in the activation of caspase-3, a terminal caspase directly involved in the execution of cell death. A peptidic inhibitor of caspase-3, Z-Asp-Glu-Val-Asp-fluoromethylketone (Z-DEVD-FMK), abrogated Rep78-induced apoptosis, indicating that Rep78-mediated apoptosis is caspase-3 dependent. Rep78 induced apoptosis in wild-type p53-containing human embryonal carcinoma NT-2 cells and in p53-null promyelocytic human HL-60 cells, indicating that at least one pathway of Rep78-induced apoptosis is p53 independent. Apoptosis was shown to occur during the G(1) and early S phases of the cell cycle. By analyzing the effects of Rep78 mutations on cell viability, the cause of cell death was attributed in part to two biochemical activities of Rep78, DNA binding and ATPase/helicase activity. The endonuclease activity of Rep78 did not contribute to apoptosis induction.
 ...
PMID:Adeno-associated virus type 2 Rep78 induces apoptosis through caspase activation independently of p53. 1100 Feb 13

To elucidate the mechanisms underlying physiological development and neurodegenerative disorders of the human brain, information about molecular cell biology of human neurons is indispensable. Necdin, which is expressed in postmitotic neurons, binds to viral oncoproteins and the cell-cycle-related transcription factors E2F and p53. Ectopic expression of necdin in proliferative cells suppresses cell division. Necdin is expressed in neurons in phylogenetically old brain areas such as the brain stem and hypothalamus. The human necdin gene, which resides in the chromosome 15q11-q12 region, is not expressed in the Prader-Willi syndrome, suggesting that necdin is responsible for the pathogenesis of this genomic-imprinting-related neurobehavioral disorder. The Alzheimer amyloid precursor protein (APP) is a membrane-bound protein that is abundantly expressed in postmitotic neurons. The proteolytic processing of APP generates A beta, which is deposited in the brains of patients with Alzheimer's disease. APP is strongly expressed in neurons in phylogenetically new brain areas such as human association cortices. When APP is overexpressed in postomitotic neurons differentiated from human embryonal carcinoma by adenovirus-mediated gene transfer, it induces typical apoptosis through caspase-3 activation. Thus APP may be a proapoptotic molecule involved in neuronal death in Alzheimer's disease.
 ...
PMID:[Molecular mechanisms of differentiation and death of human neurons: with special reference to necdin and APP]. 1121

The Alzheimer amyloid precursor protein (APP) is a transmembrane protein whose abnormal processing is associated with the pathogenesis of Alzheimer's disease. Activated caspases cleave APP and generate its carboxyl-terminally truncated fragment (APPdeltaC31). We have previously reported that overexpression of wild-type APP induces caspase-3 activation and apoptosis in postmitotic neurons. We now report that APPdeltaC31 potentially plays pathophysiological roles in neuronal death. Adenovirus-mediated overexpression of wild-type APP695 induced activation of caspase-3 and accumulation of APPdeltaC31 in postmitotic neurons derived from human NT2 embryonal carcinoma cells, whereas an APP mutant lacking the Abeta(1-20) region induced neither caspase-3 activation nor APPdeltaC31 generation. Inhibition of caspase-3 suppressed the generation of APPdeltaC31 in APP-overexpressing neurons. Forced expression of APPdeltaC31 induced apoptotic changes of neurons and non-neuronal cells, but failed to activate caspase-3. The cytotoxicity of APPdeltaC31 was also dependent on the Abeta(1-20) region. These results suggest that accumulation of wild-type APP activates neuronal caspase-3 to generate APPdeltaC31 that mediates caspase-3-independent cell death.
 ...
PMID:Cell death induced by a caspase-cleaved transmembrane fragment of the Alzheimer amyloid precursor protein. 1184 Jan 70

We have previously reported that overexpression of wild-type amyloid precursor protein (APP) in postmitotic neurons induces cleavage-dependent activation of caspase-3 both in vivo and in vitro. In this study, we investigated the mechanism underlying APP-induced caspase-3 activation using adenovirus-mediated gene transfer into postmitotic neurons derived from human embryonal carcinoma NT2 cells. Overexpression of wild-type APP significantly increased intracellular (45)Ca(2+) content prior to the activation of caspase-3 in NT2-derived neurons. Chelation of intracellular Ca(2+) markedly suppressed APP-induced activation of caspase-3. Furthermore, calpain, a Ca(2+)-dependent cysteine protease, was activated in neurons overexpressing APP as assessed by increased levels of calpain-cleaved alpha-fodrin and autolytic mu-calpain fragments. Neither calpain nor caspase-3 was activated in neurons expressing an APP mutant defective in the Abeta(1-20) domain. Calpain inhibitors almost completely suppressed APP-induced activation of neuronal caspase-3. E64d, a membrane permeable inhibitor of calpain, significantly suppressed APP-induced neuronal death. These results suggest that overexpression of wild-type APP activates calpain that mediates caspase-3 activation in postmitotic neurons.
 ...
PMID:Activation of calpain in cultured neurons overexpressing Alzheimer amyloid precursor protein. 1242 45

Excess ER stress induces caspase-12 activation and/or cytochrome c release, causing caspase-9 activation. Little is known about their relationship during ER stress-mediated cell death. Upon ER stress, P19 embryonal carcinoma (EC) cells showed activation of various caspases, including caspase-3, caspase-8, caspase-9, and caspase-12, and extensive DNA fragmentation. We examined the relationship between ER stress-mediated cytochrome c/caspase-9 and caspase-12 activation by using caspase-9- and caspase-8-deficient mouse embryonic fibroblasts and a P19 EC cell clone [P19-36/12 (-) cells] lacking expression of caspase-12. Caspase-9 and caspase-8 deficiency inhibited and delayed the onset of DNA fragmentation but did not inhibit caspase-12 processing induced by ER stress. P19-36/12 (-) cells underwent apoptosis upon ER stress, with cytochrome c release and caspase-8 and caspase-9 activation. The dominant negative form of FADD and z-VAD-fmk inhibited caspase-8, caspase-9, Bid processing, cytochrome c release, and DNA fragmentation induced by ER stress, suggesting that caspase-8 and caspase-9 are the main caspases involved in ER stress-mediated apoptosis of P19-36/12 (-) cells. Caspase-8 deficiency also inhibited the cytochrome c release induced by ER stress. Thus, in parallel with the caspase-12 activation, ER stress triggers caspase-8 activation, resulting in cytochrome c/caspase-9 activation via Bid processing.
 ...
PMID:ER stress induces caspase-8 activation, stimulating cytochrome c release and caspase-9 activation. 1258 36

The P19 mouse embryonal carcinoma cell line was used as a model for a study of apoptosis accompanying differentiation induced by all-trans retinoic acid (ATRA). Apoptosis was detected both on the basis of morphological features (nuclear fragmentation, blebbing of plasma membrane, and formation of apoptotic bodies), and by using DNA electrophoresis and flow-cytometric measurement of DNA content. Actin cytoskeleton was studied both on morphological and submicroscopic levels. ATRA-treated cells manifested apoptosis-specific changes in the distribution of actin foremost in association with their entry into executive phase of apoptosis, when F-actin cables participated in cell disintegration into apoptotic bodies. Using immunogold labeling, actin was also identified in centers of fragmenting apoptotic nuclei, in the disintegration of which it is likely involved as well. At the same time, a cleavage of actin by active caspase-3 was proved, resulting in the emergence of 32 kDa fragment, termed fractin. Measurement of F-actin and fractin content using flow cytometry showed an unequivocal decrease of F-actin and synchronous increase of fractin in the apoptotic population as compared to non-treated cells. Therefore, our results proved both actin proteolysis and active involvement of specific actin structures in the final cell disintegration during apoptosis in the P19 cells.
 ...
PMID:The role of actin in the apoptotic cell death of P19 embryonal carcinoma cells. 1614 18

Although the majority of testicular germ cell tumors (TGCTs) are curable by cisplatin-based chemotherapy, in a few cases, the occurrence of cisplatin resistance results in a poor outcome. The biological basis of this differential cisplatin sensitivity in TGCTs remains largely unexplained. Embryonal carcinoma (EC) cells represent the presumptive tumor stem cells in nonseminomatous TGCTs and are known to express the embryonal transcription factor Oct-3/4 and to be hypersensitive to cisplatin. In the present study, we analyzed TGCT cell lines and nude mouse xenografts showing differential cisplatin sensitivity. Here we demonstrate that a lack of expression of Oct-3/4 in TGCT cells is associated with a higher apoptotic threshold and cisplatin resistance which is accompanied by an impaired caspase-9 activation, reduced caspase-3 activity and altered p53 accumulation. We were able to induce loss of Oct-3/4 in a cisplatin-sensitive EC cell line resulting in a secondary cisplatin-resistant cell type with retained EC cell characteristics and changes in apoptotic signaling identical to those in primary resistant cells. Furthermore, we show that EC cells are retained in their undifferentiated state by Oct-3/4 and that a complete and ultimate loss of Oct-3/4 followed by an early differentiation step is necessary to establish the cisplatin-resistant state. Our data suggest that loss of Oct-3/4 expression leads to induction of a higher apoptotic threshold and to cisplatin resistance in EC cells of nonseminomatous TGCTs. We hypothesize that in refractory TGCTs the original tumor stem cell population of Oct-3/4-positive, cisplatin-sensitive EC cells could be replaced by an Oct-3/4-negative, resistant population in a selection process. In contrast, the presence of the Oct-3/4-positive, highly sensitive EC cells as the tumor stem cell component in most TGCTs could explain the general high chemosensitivity and curability of these tumors.
 ...
PMID:Loss of Oct-3/4 expression in embryonal carcinoma cells is associated with induction of cisplatin resistance. 1655 44


1 2 3 Next >>