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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Upon activation, cell surface death receptors, Fas/APO-1/CD95 and tumor necrosis factor receptor-1 (TNFR-1), are attached to cytosolic adaptor proteins, which in turn recruit caspase-8 (MACH/FLICE/Mch5) to activate the interleukin-1 beta-converting enzyme (ICE)/CED-3 family protease (caspase) cascade. However, it remains unknown whether these apoptotic proteases are generally involved in apoptosis triggered by other stimuli such as Myc and p53. In this study, we provide lines of evidence that a death protease cascade consisting of caspases and serine proteases plays an essential role in Myc-mediated apoptosis. When Rat-1 fibroblasts stably expressing either s-Myc or c-Myc were induced to undergo apoptosis by serum deprivation, a caspase-3 (CPP32)-like protease activity that cleaves a specific peptide substrate, Ac-DEVD-MCA, appeared in the cell lysates. Induction of s-Myc- and c-Myc-mediated apoptotic cell death was effectively prevented by caspase inhibitors such as Z-Asp-CH2-DCB and Ac-DEVD-CHO. Furthermore, exposing the cells to a serine protease inhibitor, 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF), also significantly inhibited s-Myc- and c-Myc-mediated apoptosis and the appearance of the caspase-3-like protease activity in vivo. However, AEBSF did not directly inhibit caspase-3-like protease activity in the apoptotic cell lysates in vitro. Together, these results indicate that caspase-3-like proteases play a critical role in both s-Myc- and c-Myc-mediated apoptosis and that caspase-3-like proteases function downstream of the AEBSF-sensitive step in the signaling pathway of Myc-mediated apoptosis.
Mol Cell Biol 1997 Nov
PMID:A functional role for death proteases in s-Myc- and c-Myc-mediated apoptosis. 934 38

Initiation of apopotosis requires the conversion of procaspases to mature caspases. Here we show that oligomerization of pro-caspases is sufficient to induce proteolytic generation of mature caspase subunits and activation of their cell death activity. Deletion of the protein interaction motif DED from pro-caspase-8 greatly suppresses its apoptotic activity. Cell death activity can be restored by oligomerization of pro-caspase-8 protease domains by two heterologous inducible oligomerization systems. Induced oligomerization also activates the apoptotic activity of pro-caspase-1 but not pro-caspase-3. In vitro, oligomerization leads to pro-caspase processing to from the mature caspase subunits; this processing requires the intrinsic caspase activity of zymogens and proceeds via a novel order of cleavage events.
Mol Cell 1998 Jan
PMID:Autoproteolytic activation of pro-caspases by oligomerization. 965 28

Several caspases are mediators of apoptotic cell death. We describe a novel murine member of this growing protein family. Based on homology and especially on the substrate specificity, this new procaspase is identified as the murine counterpart of human procaspase-8. The protein exhibits a rather low similarity (76%) and identity (70%) to human procaspase-8. Procaspase-8 mRNA is expressed in all adult mouse tissues examined, the highest levels being reached in kidney, liver and lung. Procaspase-8 mRNA expression is highest in seven-day old embryos, but also during later stages of development the expression was fairly high. Both human and murine procaspase-8 are very weak substrates for granzyme B as compared to procaspase-3. Murine procaspases-1, 2, 3, 6, 7, 8, 11/4 and 12 are processed by recombinant murine caspase-8, suggesting a key role in the procaspase activation cascade. In addition, murine caspase-8 induced cell death that was inhibited both by cytokine response modifier A and p35. In vitro experiments demonstrated that p35 inhibits caspase-8 directly.
J Mol Biol 1998 Dec 11
PMID:Molecular cloning and identification of murine caspase-8. 983 23

The cytosolic factor Cif (cytochrome c-efflux inducing factor) was activated by the apoptosis inducers staurosporine and anti-Fas antibodies and rapidly induced the efflux of cytochrome c from purified human mitochondria. HL-60 cells that stably overexpressed a bcl-2 cDNA transgene (Bcl-2:HL-60 cells) contained mitochondria and a cytosol that were resistant to exogenous Cif and that lacked detectable endogenous Cif activity, respectively. Therefore, Bcl-2 overexpression negated Cif activity and suggested that the requirement for Cif resides upstream of Bcl-2 on the apoptotic signal transduction pathway. The addition of purified caspase 3, caspase 7, or caspase 8 to the cytosolic extract from Bcl-2:HL-60 cells, however, restored Cif activity, demonstrating that the inhibition of Cif by Bcl-2 overexpression could be overcome by activated caspases. Moreover, the addition of purified caspases to cytosolic extracts prepared from parental HL-60 cells was also sufficient to cause Cif activation, suggesting that caspases might be required for Cif activation. Consistent with these observations, Fas-induced apoptosis in Jurkat cells resulted in caspase 8 activation and subsequently in activation of Cif. Finally, we demonstrate that the activation of Cif correlated with the activation of the Bcl-2 family member Bid by caspases and that Cif activity was selectively neutralized by anti-Bid antibodies. Taken together, these results indicate that Cif is identical to Bid and that it can be inhibited by Bcl-2 and activated by caspases. Thus, Cif (Bid) is an important biological regulator for the transduction of apoptotic signals.
Mol Cell Biol 1999 Feb
PMID:Cif (Cytochrome c efflux-inducing factor) activity is regulated by Bcl-2 and caspases and correlates with the activation of Bid. 989 Oct 71

Recent work suggests a participation of mitochondria in apoptotic cell death. This role includes the release of apoptogenic molecules into the cytosol preceding or after a loss of mitochondrial membrane potential DeltaPsim. The two uncouplers of oxidative phosphorylation carbonyl cyanide m-chlorophenylhydrazone (CCCP) and 2, 4-dinitrophenol (DNP) reduce DeltaPsim by direct attack of the proton gradient across the inner mitochondrial membrane. Here we show that both compounds enhance the apoptosis-inducing capacity of Fas/APO-1/CD95 signaling in Jurkat and CEM cells without causing apoptotic changes on their own account. This amplification occurred upstream or at the level of caspases and was not inhibited by Bcl-2. The effect could be blocked by the cowpox protein CrmA and is thus likely to require caspase 8 activity. Apoptosis induction by staurosporine in Jurkat cells as well as by Fas in SKW6 cells was unaffected by CCCP and DNP. The role of cytochrome c during Fas-DNP signaling was investigated. No early cytochrome c release from mitochondria was detected by Western blotting. Functional assays with cytoplasmic preparations from Fas-DNP-treated cells also indicated that there was no major contribution by cytochrome c or caspase 9 to the activation of effector caspases. Furthermore, an increase of rhodamine-123 uptake into intact cells, which has been explained by mitochondrial swelling, occurred considerably later than the caspase activation and was blocked by Z-VAD-fmk. These data show that uncouplers of oxidative phosphorylation can presensitize some but not all cells for a Fas death signal and provide information about the existence of separate pathways in the induction of apoptosis.
Mol Cell Biol 1999 May
PMID:Uncouplers of oxidative phosphorylation can enhance a Fas death signal. 1020 55

Recent evidence indicates that the transcription factor NF-kappaB is a major effector of inducible antiapoptotic mechanisms. For example, it was shown that NF-kappaB activation suppresses the activation of caspase 8, the apical caspase in tumor necrosis factor (TNF) receptor family signaling cascades, through the transcriptional regulation of certain TRAF and IAP proteins. However, it was unknown whether NF-kappaB controls other key regulatory mechanisms in apoptosis. Here we show that NF-kappaB activation suppresses mitochondrial release of cytochrome c through the activation of the Bcl-2 family member A1/Bfl-1. The restoration of A1 in NF-kappaB null cells diminished TNF-induced apoptosis by reducing the release of proapoptotic cytochrome c from mitochondria. In addition, A1 potently inhibited etoposide-induced apoptosis by inhibiting the release of cytochrome c and by blocking caspase 3 activation. Our findings demonstrate that A1 is an important antiapoptotic gene controlled by NF-kappaB and establish that the prosurvival function of NF-kappaB can be manifested at multiple levels.
Mol Cell Biol 1999 Sep
PMID:NF-kappaB induces expression of the Bcl-2 homologue A1/Bfl-1 to preferentially suppress chemotherapy-induced apoptosis. 1045 39

The Fas receptor (FasR) is an important physiological mediator of apoptosis in various tissues and cells. However, there are also many FasR-expressing cell types that are normally resistant to apoptotic signaling through this receptor. The mitogen-activated protein kinase (MAPK) signaling cascade has, apart from being a growth-stimulating factor, lately received attention as an inhibitory factor in apoptosis. In this study, we examined whether MAPK signaling could be involved in protecting FasR-insensitive cells. To this end, we used different approaches to inhibit MAPK signaling in HeLa cells, including treatment with the MAPK kinase inhibitor PD 98059, serum withdrawal, and expression of dominant-interfering MAPK kinase mutant protein. All of these treatments were effective in sensitizing the cells to FasR-induced apoptosis, demonstrating that MAPK indeed is involved in the control of FasR responses. The MAPK-mediated control seemed to occur at or upstream of caspase 8, the initiator caspase in apoptotic FasR responses. Transfection with the constitutively active MAPK kinase abrogated FasR-induced apoptosis also in the presence of cycloheximide, indicating that the MAPK-generated suppression of FasR-mediated apoptotic signaling is protein synthesis independent. In cells insensitive to FasR-induced apoptosis, stimulation of the FasR with an agonistic antibody resulted in significant MAPK activation, which was inhibited by PD 98059. When different cell types were compared, the FasR-mediated MAPK activation seemed proportional to the degree of FasR insensitivity. These results suggest that the FasR insensitivity is likely to be a consequence of FasR-induced MAPK activation, which in turn interferes with caspase activation.
Mol Cell Biol 1999 Sep
PMID:Inhibition of mitogen-activated kinase signaling sensitizes HeLa cells to Fas receptor-mediated apoptosis. 1045 46

The anticancer drug paclitaxel is well known as an inhibitor of microtubule depolymerization, resulting in mitosis arrest. We investigated the mechanism underlying antitumor effects of paclitaxel on the lung adenocarcinoma cell line LC-2-AD. Less than 10 microg/ml paclitaxel induced mitosis arrest upon LC-2-AD, followed by apoptosis, but more than 30 microg/ml paclitaxel induced apoptosis without mitosis arrest. LC-2-AD with less than 1 microg/ml paclitaxel showed a loss of mitochondrial transmembrane potential (deltapsim), which correlated with antitumor effects. However, LC-2-AD with more than 10 microg/ml paclitaxel showed slight changes in the loss of deltapsim in spite of its ability to induce apoptosis significantly. The cleavage of caspase 3, caspase 8, and DFF45/ICAD was also observed in paclitaxel-induced apoptosis, and the inhibitor of caspase 3 and caspase 8 inhibited both antitumor effects and apoptosis induced by paclitaxel. These results suggest that activation of caspase 3 and caspase 8 plays a crucial role in paclitaxel-induced apoptosis under any concentrations of paclitaxel.
Mol Cell Biol Res Commun 1999 Jul
PMID:A crucial role of caspase 3 and caspase 8 in paclitaxel-induced apoptosis. 1052 89

Prostate apoptosis response-4 (Par-4) is a 38-kDa protein initially identified as the product of a gene upregulated in prostate tumor cells undergoing apoptosis. Par-4 contains both a death domain and a leucine zipper domain, and has been shown to interact with several proteins known to modulate apoptosis, including protein kinase Czeta, Bcl-2, and caspase-8. A rapid increase in Par-4 levels occurs in neurons undergoing apoptosis in a variety of paradigms, including trophic factor withdrawal, and exposure to oxidative and metabolic insults. Par-4, which can be induced at the translational level, acts at an early stage of the apoptotic cascade prior to caspase activation and mitochondrial dysfunction. The mechanism whereby Par-4 promotes apoptosis may involve inhibition of the antiapoptotic transcription factor NF-kappaB and suppression of Bcl-2 expression and/or function. Studies of postmortem tissues from patients and animal models of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis (ALS), and HIV encephalitis, have documented increased levels of Par-4 in vulnerable neurons. Manipulations that block Par-4 expression or function prevent neuronal cell death in models of each disorder, suggesting a critical role for Par-4 in the neurodegenerative process. Interestingly, Par-4 levels rapidly increase in synaptic terminals following various insults, and such local increases in Par-4 levels appear to play important roles in synaptic dysfunction and degeneration. A better understanding of the molecular and cellular biology of Par-4 will help clarify mechanisms of neuronal apoptosis, and may lead to the development of novel preventative and therapeutic strategies for neurodegenerative disorders.
J Mol Neurosci
PMID:Par-4: an emerging pivotal player in neuronal apoptosis and neurodegenerative disorders. 1069 Dec 89

Cytotoxic T lymphocytes (CTL) can trigger an apoptotic signal through the Fas receptor or by the exocytosis of granzyme B and perforin. Caspase activation is an important component of both pathways. Granzyme B, a serine proteinase contained in granules, has been shown to proteolytically process and activate members of the caspase family in vitro. In order to gain an understanding of the contributions of caspases 8 and 3 during granule-induced apoptosis in intact cells, we have used target cells that either stably express the rabbitpox virus-encoded caspase inhibitor SPI-2 or are devoid of caspase 3. The overexpression of SPI-2 in target cells significantly inhibited DNA fragmentation, phosphatidylserine externalization, and mitochondrial disruption during Fas-mediated cell death. In contrast, SPI-2 expression in target cells provided no protection against granzyme-mediated apoptosis, mitochondrial collapse, or cytolysis, leading us to conclude that SPI-2-inhibited caspases are not an essential requirement for the granzyme pathway. Caspase 3-deficient MCF-7 cells were found to be resistant to CTL-mediated DNA fragmentation but not to CTL-mediated cytolysis and loss of the mitochondrial inner membrane potential. Furthermore, we demonstrate that granzyme B directly cleaves the proapoptotic molecule Bid, bypassing the need for caspase 8 activation of Bid. These results provide evidence for a two-pronged strategy for mediating target cell destruction and provide evidence of a direct link between granzyme B activity, Bid cleavage, and caspase 3 activation in whole cells.
Mol Cell Biol 2000 Jun
PMID:Granzyme B short-circuits the need for caspase 8 activity during granule-mediated cytotoxic T-lymphocyte killing by directly cleaving Bid. 1080 22


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