The BH3-Only Protein Bid Is Dispensable for DNA Damage- and Replicative Stress-Induced Apoptosis or Cell-Cycle Arrest

Kaufmann, Thomas; Tai, Lin; Ekert, Paul G.; Huang, David C.S.; Norris, Fiona; Lindemann, Ralph K.; Johnstone, Ricky W.; Dixit, Vishva M.; Strasser, Andreas

doi:10.1016/j.cell.2007.03.017

Cited by 188 publications

(201 citation statements)

References 35 publications

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“…Importantly, it has been shown that Bid is essential for CD95-induced apoptosis in hepatocytes but dispensable in thymocytes. 22,23 This indicates that CD95-mediated signaling in thymocytes can be considered as Type I, while hepatocytes can be classified as Type II cells. In addition, an important role of XIAP in the amplification of Type I signal has been reported recently.…”

Section: Cd95mentioning

confidence: 99%

Regulation of CD95/Fas signaling at the DISC

2011

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CD95 (APO-1/Fas) is a member of the death receptor (DR) family. Stimulation of CD95 leads to induction of apoptotic and nonapoptotic signaling pathways. The formation of the CD95 death-inducing signaling complex (DISC) is the initial step of CD95 signaling. Activation of procaspase-8 at the DISC leads to the induction of DR-mediated apoptosis. The activation of procaspase-8 is blocked by cellular FLICE-inhibitory proteins (c-FLIP). This review is focused on the role in the CD95-mediated signaling of the death effector domain-containing proteins procaspase-8 and c-FLIP. We discuss how dynamic cross-talk between procaspase-8 and c-FLIP at the DISC regulates life/death decisions at CD95. Open QuestionsThe exact mechanism of CD95-mediated non-apoptotic signaling is not established. The stoichiometry of the CD95 DISC is a question of future studies. New molecules may be found to be associated with the DISC. CD95Signaling CD95 (also called APO-1; Fas; fas antigen; tumor necrosis factor receptor superfamily member 6, TNFRSF6) is a member of the DR family, a subfamily of the tumor necrosis factor receptor superfamily. 1 All members of the DR family are characterized by a cytoplasmic region termed death domain (DD). 2,3 DD are 80-100 amino-acid long motifs involved in the transduction of the apoptotic signal. Crosslinking of CD95 with its natural ligand (L), CD95L (CD178) 4 or with agonistic antibodies such as anti-APO-1 5 induces apoptosis in sensitive cells.Stimulation of CD95 has been also reported to trigger nonapoptotic pathways. [6][7][8][9][10][11][12] However, details of CD95-mediated non-apoptotic pathways remain largely unknown. Importantly, it has been shown that membrane-bound CD95L is essential for the cytotoxic activity, whereas soluble CD95L appears to promote autoimmunity and tumorigenesis via induction of non-apoptotic pathways, in particular NF-kB. 13 Future studies should elucidate more details on the mechanism of nonapoptotic action of CD95L.Binding of CD95L or agonistic antibodies to CD95 leads to formation of a receptor complex at the cellular membrane, which was named DISC. 14 The DISC consists of oligomerized receptors, the DD-containing adaptor molecule FADD/MORT1 (Fas-associated DD), procaspase-8 (FLICE, MACHa, Mch5), procaspase-10 and the c-FLIP (Figure 1). [15][16][17] The interactions between the molecules at the DISC are based on homotypic contacts. The DD of the receptor interacts with the DD of FADD, whereas the death effector domain (DED) of FADD interacts with the N-terminal tandem DEDs of procaspases-8, -10 and c-FLIP. As a result of DISC formation procaspase-8 is activated at the DISC resulting in the formation of the active caspase-8, which leads to apoptosis.The initial events of DISC formation have not been clarified yet. Pre-oligomerization of CD95 via the pre-ligand assembly domain has been reported to have an important role in apoptosis initiation. 18 Recently, there have been several new reports on the X-ray structure of the complex formed by isolated CD95 and FADD DDs. 19,20 ...

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Section: Cd95mentioning

confidence: 99%

Regulation of CD95/Fas signaling at the DISC

2011

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“…Curiously, this dependence on Bid for amplification of the cell death signal has been shown to be necessary in some cell types, such as hepatocytes 195,196 , but not in others 197 .…”

Section: The Extrinsic Pathwaymentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Melanoma, the cancer derived from the melanocytes of the skin, is becoming an ever more common cancer in the ageing population of the developed world and displays an intrinsic resistance to current therapies. This chemo resistance makes metastatic melanoma an extremely difficult cancer to treat leading to a 5 year survival rate of just 20%. As such, it is important to unearth new potential drug targets to increase the prospects for melanoma patients.Bfl-1 is a pro-survival protein of the Bcl-2 family of apoptosis regulating proteins. It has been found to be over-expressed in a small subset of chemo resistant tumours, including melanoma. Accordingly, I characterised the molecule in melanoma cells and determined its role in protecting these cells from chemotherapy-induced apoptosis. I elucidated the expression profile and half-lives of the protein and mRNA across a panel of melanoma cell-lines and healthy melanocytes. I also confirmed, using pathway specific inhibitors, that Bfl-1 was transcriptionally regulated by the NFB pathway and concluded through pulsechase experiments that Bfl-1 protein was degraded, at least in part, by the proteasome. Subcellular fractionation and indirect immunofluorescence techniques elucidated that Bfl-1 was located mostly at the mitochondria in both resting and apoptotic cells, with a diffuse level present throughout the cytoplasm. As well as characterising the protein in both melanoma cells and healthy primary melanocytes, I determined its role in the resistance of these cells to apoptosis. Over-expressed Bfl-1 was found to protect melanoma cells from apoptosis caused by a range of chemotherapeutic agents in A375 melanoma cells, which naturally expressed very low levels of Bfl-1. Further, knock down of Bfl-1 using siRNA technology in melanoma cells revealed the dependence of these cells on Bfl-1 for their resistance to certain chemotherapeutic agents currently used in melanoma treatment, including the MEK inhibitor PD901. All together, this research contributes to our understanding of Bfl-1 and highlights it as a potentially important therapeutic target in metastatic melanoma.

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“…To exclude potential off-target effects of bim siRNA in the protection against excitotoxic apoptosis, we availed of a panel of gene-targeted mice deficient for various BH3-only proteins (Bouillet et al, 1999;Villunger et al, 2003;Kaufmann et al, 2007). Neocortical neurons were exposed to 100 µM NMDA for 5 min, as NMDA receptors predominantly mediate glutamate excitotoxicity in cortical neurons .…”

Section: Bim Mediates Excitotoxic Apoptosismentioning

confidence: 99%