Conversion of CD95 (Fas) Type II into Type I signaling by sub-lethal doses of cycloheximide

Brumatti, Gabriela; Yon, Monica; Castro, Fabíola Attié de; Bueno-da-Silva, A. E. B.; Jacysyn, Jacqueline F.; Brunner, Thomas; Amarante-Mendes, Gustavo P.

doi:10.1016/j.yexcr.2007.11.003

Cited by 10 publications

(7 citation statements)

References 34 publications

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“…Moreover, the K8/K18 loss leads to a direct caspase 8 activation of procaspase 3 and procaspase 9, without the involvement of the mitochondrial amplification. Alternatively, a recent study examining the conversion of Fas type II into type I cells by sub-lethal doses of cycloheximide [47] indicates that the observed conversion of type II cells is associated with a Bid down-regulation and an increased procaspase 8 activation, which is in line with the present data showing that in K8-null hepatocytes the occurrence of type-I phenotypes is related to less bid cleavage and more procaspase 8 activation. We have shown before that a K8/K18 loss leads to the disappearance of c-Flip L [29].…”

Section: Discussionsupporting

confidence: 92%

Switch in Fas-activated death signaling pathway as result of keratin 8/18-intermediate filament loss

et al. 2008

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Fas-induced apoptosis is initiated through the recruitment of FADD and procaspase 8 to form the death-inducing signaling complex (DISC). In some cells (type I cells) the initiator caspase 8 directly activates effector caspases such as procaspase 3, whereas in others (type II cells) the death signal is amplified through mitochondria. In epithelial cells, Fas-induced hierarchic caspase activation is also linked with DEDD, a member of the DED family that binds to keratin (K) intermediate filaments (IFs). Hepatocytes are type II cells and their IFs are made exclusively of K8/K18. We have shown previously that K8-null mouse hepatocytes, lacking K8/K18 IFs, are more sensitive than their wild-type counterparts to Fas-induced apoptosis. Here, by examining the cell-death kinetics and death-signaling ordering, we found that K8-null hepatocytes exhibited prominent DISC formation, higher procaspase 8 activation and direct procaspase 3 activation as reported for type I cells; however they experienced a reduced Bid cleavage and a stronger procaspase 9 activation. In addition, the K8/K18 loss altered the DEDD ubiquitination status and nuclear/cytoplasmic distribution. Together, the results suggest that the K8/K18 loss induces a switch in Fas-induced death signaling, likely through a DEDD involvement.

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Section: Discussionsupporting

confidence: 92%

Switch in Fas-activated death signaling pathway as result of keratin 8/18-intermediate filament loss

et al. 2008

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“…In addition, in type II CEM leukemia cells, cycloheximide pretreatment allowed CD95-mediated apoptosis through the direct pathway. 33 It is important to determine the generality of the mechanism defined in this study for J16-Bcl-2 cells and, in particular, whether it operates in solid tumors also. We have examined the case of HCT-15 colon carcinoma cells, as these have been well defined in terms of p53 mutant and type II status.…”

Section: Discussionmentioning

confidence: 99%

Radiation and anticancer drugs can facilitate mitochondrial bypass by CD95/Fas via c-FLIP downregulation

et al. 2009

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In many tumor cell types, ionizing radiation or DNA-damaging anticancer drugs enhance sensitivity to death receptor-mediated apoptosis, which is of clinical interest. APO010, a form of CD95/Fas ligand is currently in a phase I trial in patients with solid tumors. To analyze the potential of combined modality treatment with APO010, we used p53-mutant Jurkat T leukemic cells, in which the mitochondrial pathway was blocked by Bcl-2 overexpression. These cells were strongly sensitized to APO010 by pretreatment with ionizing -or UV radiation, etoposide, histone deacetylase -or proteasome inhibitors. These stimuli alone did not induce apoptosis in J16-Bcl-2 cells. Sensitization could not be explained by the overruling of mitochondrial resistance imposed by Bcl-2, upregulation of CD95 membrane levels or modulation of inhibitor of apoptosis proteins. Rather, the stimuli commonly downregulated c-FLIP L/S protein levels, which was causally related to the sensitization: deliberate c-FLIP L/S downregulation by RNA interference largely overruled the capacity of the various stimuli to sensitize Jurkat-Bcl-2 cells to apoptotic execution by APO010. In p53-mutant, Bcl-2 overexpressing HCT-15 colon carcinoma cells, c-FLIP downregulation correlated with sensitization to APO010 for some, but not all stimuli. We conclude that c-FLIP downregulation represents a mechanism by which diverse anticancer regimens can facilitate tumor cell execution by CD95/Fas through the direct pathway of caspase activation.

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“…8). [57][58][59][60] Thus, there is compelling Lysates were run on 4%-20% (Apaf-1 and Bnip3 L) or 10%-20% (DFFA and gAPDh) SDS-PAge gels (∼2 × 10 5 cell equivalents per lane), transferred to nitrocellulose, and the membranes probed with the appropriate rabbit polyclonal antibodies. After extensive washing, the blots were incubated with a fluorescently-labelled secondary antibody and the protein products visualized using a Odyssey infrared imager (Li-COr Biotechnology, Lincoln, ne).…”

Section: Colony Numbermentioning

confidence: 99%

Mechanisms Conferring Resistance to Pro-Apoptotic Cancer Gene Therapy

Dougherty

2011

J�Cell Death

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Recently, we have described a novel approach to the treatment of cancer that employs a series of vectors that encode surface expressed chimeric proteins in which the cytoplasmic death domain of Fas is fused in-frame to the extracellular domain of one of a number of cell surface receptors that recognize and bind various ligands that are differentially expressed within the tumor microenvironment. Although the majority of tumor cells transduced with such vectors are killed in the presence of the corresponding cognate ligand, a small percentage survive and in vivo may go on to repopulate a treated tumor. In order to understand the mechanisms employed by tumors to escape the cytotoxic effects of pro-apoptotic signals triggered via Fas, we isolated a large number of 293 tumor cell clones that survive following transfection with a plasmid vector encoding Flk-1/Fas, a chimeric receptor that induces tumor cell death in the presence of the pro-angiogenic cytokine VEGF. Characterization of Flk-1/Fas-positive clones revealed that while survival can most often be attributed simply to the down-regulation of VEGF ligand expression, in cells that express both receptor and ligand, other proteins involved in the regulation of apoptosis may be targeted. Specifically, a Flk-1/Fas-positive, VEGF-positive clone was identified in which expression of APAF-1 was almost completely abrogated.

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Conversion of CD95 (Fas) Type II into Type I signaling by sub-lethal doses of cycloheximide

Cited by 10 publications

References 34 publications

Switch in Fas-activated death signaling pathway as result of keratin 8/18-intermediate filament loss

Switch in Fas-activated death signaling pathway as result of keratin 8/18-intermediate filament loss

Radiation and anticancer drugs can facilitate mitochondrial bypass by CD95/Fas via c-FLIP downregulation

Mechanisms Conferring Resistance to Pro-Apoptotic Cancer Gene Therapy

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