The role of CD95/CD95 Ligand Signaling in Apoptosis and Cancer

Gülow, Karsten; Kamiński, Marcin M.; Krammer, Peter H.

doi:10.1002/9783527619665.ch1

Cited by 3 publications

(2 citation statements)

References 151 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, it is known that PKC is crucial for T-cell development and activation of the transcription factors AP-1 and NF-B (48,59). These transcription factors are major regulators of CD95L expression (26). In addition, AP-1 and NF-B are ROS sensitive (17).…”

Section: Discussionmentioning

confidence: 99%

Novel Role for Mitochondria: Protein Kinase Cθ-Dependent Oxidative Signaling Organelles in Activation-Induced T-Cell Death

Kamiński

Kießling

Süss

et al. 2007

Molecular and Cellular Biology

Self Cite

124

153

View full text Add to dashboard Cite

Reactive oxygen species (ROS) play a key role in regulation of activation-induced T-cell death (AICD) by induction of CD95L expression. However, the molecular source and the signaling steps necessary for ROS production are largely unknown. Here, we show that the proximal T-cell receptor-signaling machinery, including ZAP70 (zeta chain-associated protein kinase 70), LAT (linker of activated T cells), SLP76 (SH2 domaincontaining leukocyte protein of 76 kDa), PLC␥1 (phospholipase C␥1), and PKC (protein kinase C), are crucial for ROS production. PKC is translocated to the mitochondria. By using cells depleted of mitochondrial DNA, we identified the mitochondria as the source of activation-induced ROS. Inhibition of mitochondrial electron transport complex I assembly by small interfering RNA (siRNA)-mediated knockdown of the chaperone NDUFAF1 resulted in a block of ROS production. Complex I-derived ROS are converted into a hydrogen peroxide signal by the mitochondrial superoxide dismutase. This signal is essential for CD95L expression, as inhibition of complex I assembly by NDUFAF1-specific siRNA prevents AICD. Similar results were obtained when metformin, an antidiabetic drug and mild complex I inhibitor, was used. Thus, we demonstrate for the first time that PKC-dependent ROS generation by mitochondrial complex I is essential for AICD.Because CD95L expression is crucial for the induction of activation-induced T-cell death (AICD), efforts have been made to explore the connection between T-cell receptor (TCR) signaling and regulation of CD95L transcription. Following TCR engagement, ZAP70 (zeta chain-associated protein kinase 70) is activated (11). ZAP70 phosphorylates the adaptor protein LAT (linker of activated T cells) (19), which recruits PLC␥1 (phospholipase C␥1) subsequently. The activation of PLC␥1 results in the generation of inositol 3,4,5-triphosphate (IP 3 ) and diacylglycerol (DAG). IP 3 mediates an increase in cytosolic calcium (Ca 2ϩ ), whereas DAG activates protein kinase C (PKC). The rise in cytosolic Ca 2ϩ causes activation of the transcription factor NF-AT (nuclear factor of activated T cells) (69), one of the key regulators of CD95L expression (41). In addition, reactive oxygen species (ROS) are shown to be crucial for activation-induced CD95L expression (7,15,25), possibly via the ROS-inducible transcription factors NF-B and AP-1 (17). Recently, we demonstrated that a hydrogen peroxide (H 2 O 2 )-mediated signal combined with simultaneous Ca 2ϩ influx into the cytosol constitutes the minimal requirement for CD95L expression (25). However, the molecular source of TCR-induced ROS remains largely unclear. Aerobic organisms produce ROS by several means: in mitochondria as a by-product of respiration (63), at the endoplasmic reticulum by cytochrome P450 (50), in the cytoplasm by xanthine oxidase (20), at the plasma membrane by NADPH oxidases (35, 46) and phospholipases (54), and in peroxisomes (56). Recently, the phagocytic NADPH oxidase (NOX2) was shown to be one source for TCR-triggered ROS. However,...

show abstract

Section: Discussionmentioning

confidence: 99%

Novel Role for Mitochondria: Protein Kinase Cθ-Dependent Oxidative Signaling Organelles in Activation-Induced T-Cell Death

Kamiński

Kießling

Süss

et al. 2007

Molecular and Cellular Biology

Self Cite

124

153

View full text Add to dashboard Cite

show abstract

“…Twelve cell death receptors including TNF-R1, CD95 (Fas), DR3, TRAIL-R1 (tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor 1), TRAIL-R2, DR6 (death receptor 6), DcR2 (decoy receptor 2), DcR3, osteoprotegrin (OPG), oectodysplasin receptor (EDA-R), and nerve growth factor receptor (NGF-R), six death ligands TNF, CD95L (FasL), TL1A, TRAIL, EDA, and NGF have been characterized in various cellular systems (280). However, the results regarding these death receptors/ligands are limited to Fas-FasL.…”

Section: Extrinsic Receptor-mediated Apoptosis Pathwaysmentioning

confidence: 99%

Factors regulating apoptosis and homeostasis of CD4+CD25highFOXP3+ regulatory T cells are new therapeutic targets

Yang¹

2008

Front Biosci

View full text Add to dashboard Cite

CD4+ CD25(high) Foxp3+ regulatory T cells (Tregs), as an active mechanism of immune suppression, have been targeted due to their tremendous therapeutic potentials to prevent autoimmune diseases, transplant rejection, and to inhibit progression of tumors and chronic viral diseases. In last twelve years, substantial molecular differences between homeostasis of Tregs and that of other subsets of T cells and some factors specific in regulation of Treg survival have been characterized. In this overview we focus on panoramic reviewing of 91 factors, pathways and drugs, both well-characterized and newly defined, regarding the survival and homeostasis of Tregs in the following sections: 2: Tregs, an essential mechanism of immune tolerance; 3: nTregs, aTregs and other regulatory T cells; 4: co-stimulation receptor signaling; 5: innate immunity and Toll-like receptor (TLR) signaling; 6: effects of cytokines and hormones; 7: transcription factors in regulation of Tregs; 8: Treg intracellular signaling pathways; 9: drugs and potential therapeutics; and 10: Treg cell survival and death. We recently reported that removal of Tregs via a Bax-dependent apoptotic pathway significantly enhances anti-self antigen immune responses, which demonstrated for the first time the proof of principle that apoptosis of Tregs is a new therapeutic target. Therefore, continued characterization of Treg apoptosis and homeostasis pathways would further improve our understanding in regulation of immune responses by cytokines, hormones and drugs, and would also lead to development of new therapeutics.

show abstract

Improved secretion of human Fas ligand extracellular domain by N-terminal part truncation in Pichia pastoris and preparation of the N-linked carbohydrate chain trimmed derivative

Muraki

2008

Protein Expression and Purification

View full text Add to dashboard Cite

The role of CD95/CD95 Ligand Signaling in Apoptosis and Cancer

Cited by 3 publications

References 151 publications

Novel Role for Mitochondria: Protein Kinase Cθ-Dependent Oxidative Signaling Organelles in Activation-Induced T-Cell Death

Novel Role for Mitochondria: Protein Kinase Cθ-Dependent Oxidative Signaling Organelles in Activation-Induced T-Cell Death

Factors regulating apoptosis and homeostasis of CD4+CD25highFOXP3+ regulatory T cells are new therapeutic targets

Improved secretion of human Fas ligand extracellular domain by N-terminal part truncation in Pichia pastoris and preparation of the N-linked carbohydrate chain trimmed derivative

Contact Info

Product

Resources

About