Bile salts mediate hepatocyte apoptosis by increasing cell surface trafficking of Fas

Sodeman, Thomas; Bronk, Steven F.; Roberts, Patricia J.; Miyoshi, Hideyuki; Gores, Gregory J.

doi:10.1152/ajpgi.2000.278.6.g992

Cited by 188 publications

(156 citation statements)

References 30 publications

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“…An important prerequisite for Fas-mediated apoptosis appears to be trafficking of intracellular Fas to the cell surface (31,32), where cross-linking with Fas ligand leads to its oligomerization (33)(34)(35). Although the pathways responsible for Fas trafficking remain unknown, our results provide a possible mechanism for tethering Fas at the plasma membrane of kidney tubule cells after its delivery.…”

Section: Discussionmentioning

confidence: 75%

The Death Domain of Kidney Ankyrin Interacts with Fas and Promotes Fas-Mediated Cell Death in Renal Epithelia

Río¹,

Imam²,

DeLeon³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Ankyrins are a ubiquitously expressed family of conserved proteins that mediate the linkage of integral membrane proteins such as transporters and channels with the underlying cytoskeleton. Ankyrins possess a conserved death domain, the functional significance of which has remained puzzling. In this study, the death domain of AnkG190, the isoform of ankyrin expressed in kidney tubules, was used as bait in a yeast two-hybrid screen to identify interacting partners. One of these interactions was with the proapoptotic molecule Fas. This was confirmed by coimmunoprecipitation, colocalization, and glutathione S-transferase pull-down assays in cultured renal epithelial (MDCK) cells. Site-directed mutagenesis of a conserved arginine (R1496 in AnkG190), previously shown to be critical for the binding of Fas (R234 in Fas) to FADD, abolished the interaction of ankyrin's death domain with Fas. Overexpression of constructs containing ankyrin's death domain promoted Fas-mediated apoptosis in MDCK cells. The linkage between ankyrin and Fas was confirmed in vivo in mouse kidney tubule cells by coimmunoprecipitation and colocalization. In an established mouse model of renal ischemia-reperfusion injury characterized by apoptotic tubule cell death, the expression of both ankyrin and Fas was markedly induced, and the interaction between these molecules remained intact. The results identify a novel tethering interaction between ankyrin and Fas in kidney epithelia and suggest that AnkG190 may play a role as an adapter molecule in renal tubule cell death.Tethering interactions between membrane proteins and the underlying spectrin-based cytoskeleton play key roles in several cellular activities, including organization of plasma membrane domains (1

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Section: Discussionmentioning

confidence: 75%

The Death Domain of Kidney Ankyrin Interacts with Fas and Promotes Fas-Mediated Cell Death in Renal Epithelia

Río¹,

Imam²,

DeLeon³

et al. 2004

Journal of the American Society of Nephrology

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“…The fact that the difference in Fas membrane Inhibition of indomethacin-induced apoptosis. Apoptosis induction in GLG 4 -Adr after exposure to 50 mM indomethacin (grey) or 0 mM indomethacin (black) in combination with the caspase-8 inhbitor zIETD-fmk, the caspase-9 inhibitor zLEHD or the broad-spectrum caspase inhibitor zVAD-fmk for 24 h. Indomethacin circumvents doxorubicin resistance DJA de Groot et al expression does not correlate with the Fas expression in total cell lysates may be due to a different distribution of Fas, cytoplasmic and on the cell membrane, as was described in prostate carcinoma cell lines and neuroblastoma cell lines Usla et al, 1997;Bennett et al, 1998;Sodeman et al, 2000). The expression levels of the proapoptotic proteins caspase-8 and Bid were also elevated in GLC 4 -Adr compared to GLC 4 .…”

Section: Discussionmentioning

confidence: 99%

Indomethacin-induced activation of the death receptor-mediated apoptosis pathway circumvents acquired doxorubicin resistance in SCLC cells

et al. 2005

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Small-cell lung cancers (SCLCs) initially respond to chemotherapy but are often resistant at recurrence. A potentially new method to overcome resistance is to combine classical chemotherapeutic drugs with apoptosis induction via tumour necrosis factor (TNF) death receptor family members such as Fas. The doxorubicin-resistant human SCLC cell line GLC 4 -Adr and its parental doxorubicinsensitive line GLC 4 were used to analyse the potential of the Fas-mediated apoptotic pathway and the mitochondrial apoptotic pathway to modulate doxorubicin resistance in SCLC. Western blotting showed that all proteins necessary for death-inducing signalling complex formation and several inhibitors of apoptosis were expressed in both lines. The proapototic proteins Bid and caspase-8, however, were higher expressed in GLC 4 -Adr. In addition, GLC 4 -Adr expressed more Fas (3.1x) at the cell membrane. Both lines were resistant to anti-Fas antibody, but plus the protein synthesis inhibitor cycloheximide anti-Fas antibody induced 40% apoptosis in GLC 4 -Adr. Indomethacin, which targets the mitochondrial apoptotic pathway, induced apoptosis in GLC 4 -Adr but not in GLC 4 cells. Surprisingly, in GLC 4 -Adr indomethacin induced caspase-8 and caspase-9 activation as well as Bid cleavage, while both caspase-8 and caspase-9 specific inhibitors blocked indomethacin-induced apoptosis. In GLC 4 -Adr, doxorubicin plus indomethacin resulted in elevated caspase activity and a 2.7-fold enhanced sensitivity to doxorubicin. In contrast, no effect of indomethacin on doxorubicin sensitivity was observed in GLC 4 . Our findings show that indomethacin increases the cytotoxic activity of doxorubicin in a doxorubicin-resistant SCLC cell line partly via the death receptor apoptosis pathway, independent of Fas.

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“…These data suggested the sensitivity of HepG2 by CYP2E1 to FasL is caspasesdependent, but not due to elevating Fas expression or effecting translocation of cytoplasmic Fas to the cell surface. 28 CYP2E1 plays a central role in the induction of oxidative stress, which involve in lipid peroxidation, protein oxidative, nitrosative stress, and a decrease in hepatic antioxidant defense. These indexes of oxidant stress were verified to be associated with alcohol/Jo2-induced liver injury.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of CYP2E1 enhances sensitivity of HepG2 cells to Fas-mediated cytotoxicity

Shi²,

Zhang³

et al. 2008

Cancer Biology & Therapy

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Bile salts mediate hepatocyte apoptosis by increasing cell surface trafficking of Fas

Cited by 188 publications

References 30 publications

The Death Domain of Kidney Ankyrin Interacts with Fas and Promotes Fas-Mediated Cell Death in Renal Epithelia

The Death Domain of Kidney Ankyrin Interacts with Fas and Promotes Fas-Mediated Cell Death in Renal Epithelia

Indomethacin-induced activation of the death receptor-mediated apoptosis pathway circumvents acquired doxorubicin resistance in SCLC cells

Overexpression of CYP2E1 enhances sensitivity of HepG2 cells to Fas-mediated cytotoxicity

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