Molecular ordering of hypoxia-induced apoptosis: critical involvement of the mitochondrial death pathway in a FADD/caspase-8 independent manner

Fas (APO-1/CD95) is the prototypic death receptor, and the molecular mechanisms of Fas-induced apoptosis are comparably well understood. Here, we show that Fas activates NFκB via a pathway involving RIP, FADD, and caspase-8. Remarkably, the enzymatic activity of the latter was dispensable for Fas-induced NFκB signaling pointing to a scaffolding-related function of caspase-8 in nonapoptotic Fas signaling. NFκB was activated by overexpressed FLIPL and FLIPS in a cell type–specific manner. However, in the context of Fas signaling both isoforms blocked FasL-induced NFκB activation. Moreover, down-regulation of both endogenous FLIP isoforms or of endogenous FLIPL alone was sufficient to enhance FasL-induced expression of the NFκB target gene IL8. As NFκB signaling is inhibited during apoptosis, FasL-induced NFκB activation was most prominent in cells that were protected by Bcl2 expression or caspase inhibitors and expressed no or minute amounts of FLIP. Thus, protection against Fas-induced apoptosis in a FLIP-independent manner converted a proapoptotic Fas signal into an inflammatory NFκB-related response.

Download Full-text

Apoptotic Response of Chang Cells to Infection with Pseudomonas aeruginosa Strains PAK and PAO-I: Molecular Ordering of the Apoptosis Signaling Cascade and Role of Type IV Pili

Infection and Immunity ◽

10.1128/iai.71.5.2665-2673.2003 ◽

2003 ◽

Vol 71 (5) ◽

pp. 2665-2673 ◽

Cited By ~ 29

Author(s):

Verena Jendrossek ◽

Sophie Fillon ◽

Claus Belka ◽

Ilka Müller ◽

Beatrice Puttkammer ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Epithelial Cells ◽

Host Cells ◽

Caspase 8 ◽

Mitochondrial Alterations ◽

Human Epithelial Cells ◽

Molecular Ordering ◽

Induced Apoptosis ◽

Chang Cells

ABSTRACT Pseudomonas aeruginosa is a gram-negative facultative opportunistic pathogen associated with severe infections in immunocompromised hosts and in patients with cystic fibrosis. P. aeruginosa strains show divergent pathogenicity in vivo and trigger apoptosis of and/or are internalized into human host cells. In the present study, we studied the molecular ordering of apoptosis signaling upon infection of human conjunctiva epithelial Chang cells with P. aeruginosa PAK as well as the role of bacterial pili in the response to the infection. Our results show that CD95 up-regulation is followed by early activation of caspase-8 and -3 and cleavage of the caspase-3 substrate poly(ADP-ribose) polymerase. The data also demonstrate release of apoptosis inducing factor into the cytosol of infected cells. Induction of mitochondrial alterations, i.e., mitochondrial depolarization and release of cytochrome c, as well as cleavage of caspase-9, -7, and -1 occurred only at later time points. In addition, our results demonstrate that pili are required for P. aeruginosa-induced apoptosis of human epithelial cells. While the two piliated P. aeruginosa strains, PAO-I and PAK, induced apoptosis of Chang cells within 3 h of infection, the pilus-deficient P. aeruginosa mutants PAKΔpilA and PAKΔpilAΔall were without effect. The pilus-deficient mutants failed to induce a significant up-regulation of CD95 on the cell surface and to trigger mitochondrial alterations or activation of caspase-8, -3, and -7. In addition, only the piliated wild-type strains induced caspase-1-mediated activation of interleukin-1β. Thus, pili are necessary for distinct infection-induced cellular responses of human epithelial cells.

Download Full-text

Faculty Opinions recommendation of Dexamethasone-induced apoptosis of thymocytes: role of glucocorticoid receptor-associated Src kinase and caspase-8 activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1012030.183870 ◽

2003 ◽

Author(s):

Guy Laurent

Keyword(s):

Glucocorticoid Receptor ◽

Src Kinase ◽

Caspase 8 ◽

Induced Apoptosis

Download Full-text

Faculty Opinions recommendation of Caspase-8 can be activated by interchain proteolysis without receptor-triggered dimerization during drug-induced apoptosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1023131.266647 ◽

2005 ◽

Author(s):

David Wallach

Keyword(s):

Caspase 8 ◽

Drug Induced ◽

Induced Apoptosis

Download Full-text

Cinnamaldehyde-Induced Apoptosis in Human Hepatoma PLC/PRF/5 Cells Involves the Mitochondrial Death Pathway and is Sensitive to Inhibition by Cyclosporin A and z-VAD-fmk

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/18715206113139990144 ◽

2013 ◽

Vol 13 (10) ◽

pp. 1565-1574 ◽

Cited By ~ 19

Author(s):

Liang-Tzung Lin ◽

Chen-Jei Tai ◽

Shun-Pang Chang ◽

Jin-Liang Chen ◽

Shu-Jing Wu ◽

...

Keyword(s):

Cyclosporin A ◽

Human Hepatoma ◽

Mitochondrial Death Pathway ◽

Induced Apoptosis

Download Full-text

Glucocorticoid Receptor β (GRβ): Beyond Its Dominant-Negative Function

International Journal of Molecular Sciences ◽

10.3390/ijms22073649 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3649

Author(s):

Patricia Ramos-Ramírez ◽

Omar Tliba

Keyword(s):

Current Knowledge ◽

Inflammatory Diseases ◽

Cell Communication ◽

Cell Types ◽

The Body ◽

Dominant Negative ◽

Negative Effects ◽

Independent Manner ◽

Distinct Cell ◽

Induced Apoptosis

Glucocorticoids (GCs) act via the GC receptor (GR), a receptor ubiquitously expressed in the body where it drives a broad spectrum of responses within distinct cell types and tissues, which vary in strength and specificity. The variability of GR-mediated cell responses is further extended by the existence of GR isoforms, such as GRα and GRβ, generated through alternative splicing mechanisms. While GRα is the classic receptor responsible for GC actions, GRβ has been implicated in the impairment of GRα-mediated activities. Interestingly, in contrast to the popular belief that GRβ actions are restricted to its dominant-negative effects on GRα-mediated responses, GRβ has been shown to have intrinsic activities and “directly” regulates a plethora of genes related to inflammatory process, cell communication, migration, and malignancy, each in a GRα-independent manner. Furthermore, GRβ has been associated with increased cell migration, growth, and reduced sensitivity to GC-induced apoptosis. We will summarize the current knowledge of GRβ-mediated responses, with a focus on the GRα-independent/intrinsic effects of GRβ and the associated non-canonical signaling pathways. Where appropriate, potential links to airway inflammatory diseases will be highlighted.

Download Full-text